Benzylic oxindole pyrimidines

ABSTRACT

The present invention encompasses compounds of general formula (I) 
     
       
         
         
             
             
         
       
     
     wherein the groups R 5  to R 10 , A, L 1 , B, m and p are defined as in claim  1 , which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, pharmaceutical preparations which contain such compounds and their use as medicaments.

The present invention relates to new benzylic oxindolepyrimidines ofgeneral formula (I)

wherein the groups R⁵ to R¹⁰, A, L¹, B, m and p have the meanings givenin the claims and specification, which are suitable for the treatment ofdiseases characterised by excessive or abnormal cell proliferation,pharmaceutical preparations which contain such compounds and their useas medicaments. The compounds according to the invention display aninhibitory effect on the phosphorylation activity of the IGF-1 receptorlocated in cell membranes.

BACKGROUND TO THE INVENTION

WO 2006/021544 describes diamino-substituted pyrimidines that carry bi-and tricyclic substituents in position 4 of the pyrimidine ring, as PLK1inhibitors.

WO 2004/080980 describes diamino-substituted pyrimidines that carryinter alia bicyclic substituents in position 4 of the pyrimidine ring,as IGF-1R inhibitors.

The aim of the present invention is to indicate new compounds which canbe used for the prevention and/or treatment of diseases characterised byexcessive or abnormal cell proliferation. The compounds according to theinvention are characterised by a powerful inhibitory effect on thephosphorylation activity of the IGF-1 receptor located in cell membranesand a potent efficacy against tumour cells, e.g. glioblastoma cells,which is mediated through the inhibition of phosphorylation of thereceptor. In addition to the inhibitory effect and cell activity thecompounds have good solubility and good PK properties and goodselectivity over other kinases (Invitrogen panel).

The insulin-like growth factor (IGF) and insulin signalling network is ahighly conserved and essential pathway involved in biological processesincluding growth, metabolism and homeostasis. In addition, deregulatedsignalling via this network can enhance tumorigenesis and metastasis ofcertain cancers.

The ligands IGF-1, IGF-2 and insulin are highly homologous and activatespecific hetero or homodimers of the IGF-1R and IR. Following ligandbinding, the IGF-1R and IR undergo autophosphorylation mediated via thereceptor tyrosine kinase domains. The phosphorylated receptors activatethe canonical Ras-Raf-MEK-ERK1/2 and PI3K- PDK1-Akt intracellularsignaling cascades, which leads to cell proliferation and survival. Inaddition, activation of the IR by insulin stimulates the uptake ofglucose and storage of glycogen in metabolic tissues such as the liver,adipose and muscle.

Published research articles as well as medical and epidemiologicalinvestigations have identified a strong correlation between expressionof the IGF-1R and IR and ligands for these receptors in tumordevelopment and progression. Developing a small molecule competitiveinhibitor of the ATP-binding pocket of the IGF-1R and IR as a means ofblocking growth and survival signaling cascades in cancer is thereforedesirable. The anticipated clinical benefit of blocking such aninteraction would be to reduce tumor growth rate and potentiallysensitize tumors to cytotoxic agents or targeted therapies.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly it has been found that compounds of general formula (I),wherein the groups R⁵ to R¹⁰, A, L¹, B, m and p have the meanings statedhereinafter, act as inhibitors of receptors that are involved incontrolling cell proliferation. Thus, the compounds according to theinvention may be used for example for the treatment of diseasesassociated with the activity of these receptors and characterised byexcessive or abnormal cell proliferation.

The present invention therefore relates to compounds of general formula(I)

wherein

(A0)

R⁵ is selected from among trifluoromethyl and halogen;

(B0)

R⁶, R⁷ and R⁸ are each independently selected from among hydrogen andC₁₋₄alkyl orR⁶ and R⁷ together with the carbon atom to which they bond form asaturated, 3-5 membered hydrocarbon ring;

(C0)

ring system A is selected from among C₆₋₁₀aryl, 3-14 memberedheterocyclyl and 5-12 membered heteroaryl;

(D0)

each R⁹ is independently selected in each case from among C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, halogen and—CN;m denotes 0, 1, 2 or 3;

(E0)

L¹ is selected from among a bond, —(CH₂)_(n)—O, —(CH₂)_(n)—NH,—(CH₂)_(n)—NH—C(O), —(CH₂)_(n)—C(O)—NH, —(CH₂)_(n)— and—(CH₂)_(n)—C(O),while in the present nomenclature the linker group L¹ on the right bindsto the ring system A;n denotes 0, 1, 2 or 3;

(F0)

ring system B is selected from among 4-10 membered, saturated orunsaturated heterocyclyl and phenyl;

(G0)

each R¹⁰ is independently selected in each case from among R^(a) andR^(b);p denotes 0, 1, 2 or 3;each R^(a) independently denotes a group optionally substituted by oneor more identical or different R^(b) and/or R^(c) selected from amongC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl,C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl;each R^(b) is independently selected in each case from among —OR^(c),—SR^(c), —NR^(c)R^(c), halogen, —CN, —NO₂, —C(O)R^(c), —C(O)OR^(c),—C(O)NR^(c)R^(c), —C(NR^(f))NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c),—S(O)₂R^(c), —S(O)₂NR^(c)R^(c), —NR^(f)C(O)R^(c), —NR^(f)C(O)OR^(c),—NR^(f)C(O)NR^(c)R^(c), —NR¹C(NR^(f))NR^(c)R^(c) and —NR^(f)S(O)₂R^(c),as well as the bivalent substituent ═O, while the latter may only be asubstituent in non-aromatic ring systems;each R^(c) independently denotes hydrogen or a group optionallysubstituted by one or more identical or different R^(d) and/or R^(e)selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryland 3-14 membered heterocyclyl;each R^(d) is independently selected in each case from among —OR^(e),—SR^(e), —NR^(e)R^(e), halogen, —CN, —NO₂, —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(e)R^(e), —C(NR^(f))NR^(e)R^(e), —OC(O)R^(e), —OC(O)OR^(e),—S(O)₂R^(e), —S(O)₂NR^(e)R^(e), —NR^(f)C(O)R^(e), —NR^(f)C(O)OR^(e),—NR^(f)C(O)NR^(e)R^(e), —NR^(f)C(NR^(f))NR^(e)R^(e) and—NR^(f)S(O)₂R^(e), as well as the bivalent substituent ═O, while thelatter may only be a substituent in non-aromatic ring systems;each R^(e) independently denotes hydrogen or a group optionallysubstituted by one or more identical or different R^(f) selected fromamong C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl,C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 memberedheterocyclyl, and

each R^(f) is independently selected in each case from among hydrogenand C₁₋₆alkyl,

while the compounds (I) may optionally also occur in the form of theirtautomers, racemates, enantiomers, diastereomers or mixtures thereof, oras the respective salts of all the above-mentioned forms.

The present invention further relates to compounds of general formula(I)

wherein

(A0)

R⁵ is selected from among trifluoromethyl and halogen;

(B0)

R⁶, R⁷ and R⁸ are independently selected in each case from amonghydrogen and C₁₋₄alkyl orR⁶ and R⁷ together with the carbon atom to which they bond forms asaturated, 3-5 membered hydrocarbon ring;

(C0)

ring system A is selected from among C₆₋₁₀aryl and 5-12 memberedheteroaryl;

(D0)

each R⁹ is independently selected in each case from among C₁₋₆alkyl,C₁₋₆alkoxy, halogen and —CN;m denotes 0, 1, 2 or 3;

(E0)

L¹ is selected from among a bond, —(CH₂)_(n)—O, —(CH₂)_(n)—NH,—(CH₂)_(n)—NH—C(O), —(CH₂)_(n)—C(O)—NH, —(CH₂)_(n)— and —(CH₂)_(n)—C(O),while in the present nomenclature the linker group L¹ on the right bindsto the ring system A;n denotes 0, 1, 2 or 3;

(F0)

ring system B is selected from among 4-10 membered, saturated orunsaturated heterocyclyl and phenyl;

(G0)

each R¹⁰ is independently selected in each case from among R^(a) andR^(b);p denotes 0, 1, 2 or 3;each R^(a) independently denotes a group optionally substituted by oneor more identical or different R^(b) and/or R^(c) selected from amongC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl,C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl;each R^(b) is independently selected in each case from among —OR^(c),—SR^(c), —NR^(c)R^(c), halogen, —CN, —NO₂, —C(O)R^(c), —C(O)OR^(c),—C(O)NR^(c)R^(c), —C(NR^(f))NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c),—S(O)₂R^(c), —S(O)₂NR^(c)R^(c), —NR^(f)C(O)R^(c), —NR^(f)C(O)OR^(c),—NR^(f)C(O)NR^(c)R^(c), —NR^(f)C(NR^(f))NR^(c)R^(c) and—NR^(f)S(O)₂R^(c), as well as the bivalent substituent ═O, while thelatter may only be a substituent in non-aromatic ring systems;each R^(c)C independently denotes hydrogen or a group optionallysubstituted by one or more identical or different R^(d) and/or R^(e)selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryland 3-14 membered heterocyclyl;each R^(d) is independently selected in each case from among —OR^(e),—SR^(e), —NR^(e)R^(e), halogen, —CN, —NO₂, —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(e)R^(e), —C(NR^(f))NR^(e)R^(e), —OC(O)R^(e), —OC(O)OR^(e),—S(O)₂R^(e), —S(O)₂NR^(e)R^(e), —NR^(f)C(O)R^(e), —NR^(f)C(O)OR^(e),—NR^(f)C(O)NR^(e)R^(e), —NR^(f)C(NR^(f))NR^(e)R^(e) and—NR^(f)S(O)₂R^(e), as well as the bivalent substituent ═O, while thelatter may only be a substituent in non-aromatic ring systems;each R^(e) independently denotes hydrogen or a group optionallysubstituted by one or more identical or different R^(f) selected fromamong C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl,C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 memberedheterocyclyl, andeach R^(f) is independently selected in each case from among hydrogenand C₁₋₆alkyl,while the compounds (I) may optionally also occur in the form of theirtautomers, racemates, enantiomers, diastereomers or mixtures thereof, oras the respective salts of all the above-mentioned forms.

In one aspect (A1) the invention relates to compounds (I), wherein

R⁵ denotes trifluoromethyl.

In one aspect (A2) the invention relates to compounds (I), wherein

R⁵ denotes chlorine.

In one aspect (A3) the invention relates to compounds (I), wherein

R⁵ denotes bromine.

In another aspect (B1) the invention relates to compounds (I), wherein

R⁶ and R⁷ in each case denote methyl and R⁸ denotes hydrogen.

In another aspect (B2) the invention relates to compounds (I), wherein

R⁶, R⁷ and R⁸ in each case denote hydrogen.

In another aspect (B3) the invention relates to compounds (I), wherein

R⁶ and R⁷ together with the carbon atom to which they bond form acyclopropyl ring andR⁸ denotes hydrogen.

In another aspect (C1) the invention relates to compounds (I), wherein

ring system A is selected from among phenyl and 5-6 membered heteroaryl.

In another aspect (C2) the invention relates to compounds (I), wherein

ring system A is a phenyl.

In another aspect (C3) the invention relates to compounds (I), wherein

ring system A is a 5-6 membered, nitrogen-containing heteroaryl.

In another aspect (C4) the invention relates to compounds (I), wherein

ring system A is a pyridyl or pyrazolyl.

In another aspect (D1) the invention relates to compounds (I) wherein

m has the value 0.

In another aspect (D2) the invention relates to compounds (I), wherein

m has the value 1 or 2 andR⁹ is selected from among halogen, C₁₋₄alkyl and C₁₋₄alkoxy.

In another aspect (D3) the invention relates to compounds (I), wherein

m has the value 1 or 2 andR⁹ is selected from among C₁₋₄alkyl and C₁₋₄alkoxy.

In another aspect (D4) the invention relates to compounds (I), wherein

m has the value 1 or 2 andR⁹ is selected from among methyl, ethyl, methoxy and ethoxy.

In another aspect (CD1) the invention relates to compounds (I), wherein

ring system A and the m groups R⁹ together denote

R^(9a) is selected from among hydrogen, C₁₋₄alkyl and C₁₋₄alkoxy andR^(9b) is selected from among hydrogen and C₁₋₄alkyl.

In another aspect (CD2) the invention relates to compounds (I), wherein

ring system A and the m groups R⁹ together denote

R^(9a) is selected from among C₁₋₄alkyl and C₁₋₄alkoxy andR^(9b) is selected from among hydrogen and C₁₋₄alkyl.

In another aspect (CD3) the invention relates to compounds (I), wherein

ring system A and the m groups R⁹ together denote

R^(9a) is selected from among hydrogen, methyl, ethyl, methoxy andethoxy andR^(9b) is selected from among hydrogen, methyl and ethyl.

In another aspect (CD4) the invention relates to compounds (I), wherein

ring system A and the m groups R⁹ together denote

R^(9a) is selected from among methyl, ethyl, methoxy and ethoxy andR^(9b) is selected from among hydrogen, methyl and ethyl.

In another aspect (CD5) the invention relates to compounds (I), wherein

ring system A and the m groups R⁹ together denote

In another aspect (E1) the invention relates to compounds (I), wherein

L¹ is selected from among a bond, —(CH₂)₂—O, —NH—C(O), —C(O)—NH— and—C(O), while in the present nomenclature the linker group L¹ on theright binds to the ring system A.

In another aspect (E2) the invention relates to compounds (I), wherein

L¹ corresponds to a bond.

In another aspect (E3) the invention relates to compounds (I), wherein

L¹ is selected from among —(CH₂)₂—O, —NH—C(O)— and —C(O)—.

In another aspect (F1) the invention relates to compounds (I), wherein

ring system B is a 4-10 membered, saturated or unsaturated heterocyclyl.

In another aspect (F2) the invention relates to compounds (I), wherein

ring system B is a 5-7 membered, saturated and nitrogen-containingheterocyclyl.

In another aspect (F3) the invention relates to compounds (I), wherein

ring system B is selected from among piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl and 2,5-diaza-bicyclo[2,2,1]heptyl.

In another aspect (G1) the invention relates to compounds (I), wherein

p has the value 0.

In another aspect (G2) the invention relates to compounds (I), wherein

p has the value 1 or 2;

each R¹⁰ is independently selected in each case from among R^(a) andR^(b);

each R^(a) independently denotes a group optionally substituted by oneor more identical or different R^(b) and/or R^(c) selected from amongC₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-14 membered heterocyclyl;each R^(b) is independently selected in each case from among —OR^(c),—NR^(c)R^(c), halogen, —CN, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c),—S(O)₂R^(c) and —S(O)₂NR^(c)R^(c), as well as the bivalent substituent═O, while the latter may only be a substituent in non-aromatic ringsystems;each R^(c) independently denotes hydrogen or a group optionallysubstituted by one or more identical or different R^(d) and/or R^(e)selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, 5-12 membered heteroaryland 3-14 membered heterocyclyl;each R^(d) is independently selected in each case from among —OR^(e),—NR^(e)R^(e), —CN, —C(O)R^(e), —C(O)OR^(e) and —NR^(f)C(O)OR^(e), aswell as the bivalent substituent ═O, while the latter may only be asubstituent in non-aromatic ring systems;each R^(e) independently denotes hydrogen or a group optionallysubstituted by one or more identical or different R^(f) selected fromamong C₁₋₆alkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 memberedheterocyclyl, andeach R^(f) is independently selected in each case from among hydrogenand C₁₋₆alkyl.

In another aspect (G3) the invention relates to compounds (I), wherein

p has the value 1 or 2,each R¹⁰ is independently selected in each case from among R^(a) andR^(b);each R^(a) independently denotes a group optionally substituted by oneor more identical or different R^(b) and/or R^(c) selected from amongC₁₋₆alkyl, C₃₋₆cycloalkyl and 4-7 membered heterocyclyl;each R^(b) is independently selected in each case from among —OR^(c),—NR^(c)R^(c), halogen, —CN, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c),—S(O)₂R^(c) and —S(O)₂NR^(c)R^(c), as well as the bivalent substituent═O, while the latter may only be a substituent in non-aromatic ringsystems;each R^(c) independently denotes hydrogen or a group optionallysubstituted by one or more identical or different R^(d) and/or R^(e)selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryland 4-7 membered heterocyclyl;each R^(d) is independently selected in each case from among —OR^(e),—NR^(e)R^(e), —CN, —C(O)R^(e), —C(O)OR^(e) and —NR^(f)C(O)OR^(e), aswell as the bivalent substituent ═O, while the latter may only be asubstituent in non-aromatic ring systems;each R^(e) independently denotes hydrogen or a group optionallysubstituted by one or more identical or different R^(f) selected fromamong C₁₋₆alkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocyclyl, andeach R^(f) is independently selected in each case from among hydrogenand C₁₋₆alkyl.

In another aspect (FG1) the invention relates to compounds (I), wherein

ring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among R^(a) andR^(b);each R^(a) independently denotes a group optionally substituted by oneor more identical or different R^(b) and/or R^(c)C selected from amongC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl,C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl;each R^(b) is independently selected in each case from among —OR^(c),—SR^(c), —NR^(c)R^(c), halogen, —CN, —NO₂, —C(O)R^(c), —C(O)OR^(c),—C(O)NR^(c)R^(c), —C(NR^(f))NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c),S(O)₂R^(c), —S(O)₂NR^(c)R^(c), —NR^(f)C(O)R^(c), —NR^(f)C(O)OR^(c),—NR^(f)C(O)NR^(c)R^(c), —NR^(f)C(NR^(f))NR^(c)R^(c) and—NR^(f)S(O)₂R^(c), as well as the bivalent substituent ═O, while thelatter may only be a substituent in non-aromatic ring systems;each R^(c) independently denotes hydrogen or a group optionallysubstituted by one or more identical or different R^(d) and/or R^(e)selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryland 3-14 membered heterocyclyl;each R^(d) is independently selected in each case from among —OR^(e),—SR^(e), —NR^(e)R^(e), halogen, —CN, —NO₂, —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(e)R^(e), —C(NR^(f))NR^(e)R^(e), —OC(O)R^(e), —OC(O)OR^(e),—S(O)₂R^(e), —S(O)₂NR^(e)R^(e), —NR^(f)C(O)R^(e), —NR^(f)C(O)OR^(e),—NR^(f)C(O)NR^(e)R^(e), —NR^(f)C(NR^(f))NR^(e)R^(e) and—NR^(f)S(O)₂R^(e), as well as the bivalent substituent ═O, while thelatter may only be a substituent in non-aromatic ring systems;each R^(e) independently denotes hydrogen or a group optionallysubstituted by one or more identical or different R^(f) selected fromamong C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl,C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 memberedheterocyclyl, andeach R^(f) is independently selected in each case from among hydrogenand C₁₋₆alkyl.

In another aspect (FG2) the invention relates to compounds (I), wherein

ring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among R^(a) andR^(b);each R^(a) independently denotes a group optionally substituted by oneor more identical or different R^(b) and/or R^(c) selected from amongC₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-14 membered heterocyclyl;each R^(b) is independently selected in each case from among —OR^(c),—NR^(c)R^(c), halogen, —CN, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c),—S(O)₂R^(c) and —S(O)₂NR^(c)R^(c), as well as the bivalent substituent═O, while the latter may only be a substituent in non-aromatic ringsystems;each R^(c) independently denotes hydrogen or a group optionallysubstituted by one or more identical or different R^(d) and/or R^(e)selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, 5-12 membered heteroaryland 3-14 membered heterocyclyl;

each R^(d) is independently selected in each case from among —OR^(e),—NR^(e)R^(e), —CN, —C(O)R^(e), —C(O)OR^(e) and —NR^(f)C(O)OR^(e), aswell as the bivalent substituent ═O, while the latter may only be asubstituent in non-aromatic ring systems;

each R^(e) independently denotes hydrogen or a group optionallysubstituted by one or more identical or different R^(f) selected fromamong C₁₋₆alkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 memberedheterocyclyl, and

each R^(f) is independently selected in each case from among hydrogenand C₁₋₆alkyl.

In another aspect (FG3) the invention relates to compounds (I), whereinring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among R^(a) andR^(b);each R^(a) independently denotes a group optionally substituted by oneor more identical or different R^(b) and/or R^(c) selected from amongC₁₋₆alkyl, C₃₋₆cycloalkyl and 4-7 membered heterocyclyl;each R^(b) is independently selected in each case from among —OR^(c),—NR^(c)R^(c), halogen, —CN, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c),—S(O)₂R^(c) and —S(O)₂NR^(c)R^(c), as well as the bivalent substituent═O, while the latter may only be a substituent in non-aromatic ringsystems;

each R^(c)C independently denotes hydrogen or a group optionallysubstituted by one or more identical or different R^(d) and/or R^(e)selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryland 4-7 membered heterocyclyl;

each R^(d) is independently selected in each case from among —OR^(e),—NR^(e)R^(e), —CN, —C(O)R^(e), —C(O)OR^(e) and —NR^(f)C(O)OR^(e), aswell as the bivalent substituent ═O, while the latter may only be asubstituent in non-aromatic ring systems;each R^(e) independently denotes hydrogen or a group optionallysubstituted by one or more identical or different R^(f) selected fromamong C₁₋₆alkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocyclyl, andeach R^(f) is independently selected in each case from among hydrogenand C₁₋₆alkyl.

In another aspect (FG4) the invention relates to compounds (I), wherein

ring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among—C(O)—C₁₋₄alkyl, hydrogen, C₁₋₆alkyl (CN), C₁₋₆haloalkyl—C(O)—O—C₁₋₄alkyl, —COOH, (C₁₋₄alkyl)₂N—C₁₋₄alkylene-C(O),(C₁₋₄alkyl)NH—C₁₋₄alkylene-C(O), H₂N—C₁₋₄alkylene-C(O),HO—C₁₋₄alkylene-C(O), —C(O)—N(C₁₋₄alkyl)₂, —C(O)—NH(C₁₋₄alkyl),—C(O)NH₂, C₁₋₄alkyl-O—C₁₋₄alkylene-C(O), 4-6 membered heterocyclyl(optionally substituted by C₁₋₄alkyl, C₃₋₆cycloalkyl or 3-6 memberedheterocyclyl), C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl, HO—C₂₋₄alkyl,C₁₋₄alkyl-O—C₂₋₄alkyl, HO—C₂₋₄haloalkyl, C₁₋₄alkyl-S(O)₂,C₁₋₄alkyl-NH—C(O)—C₁₋₄alkyl, H₂N—C(O)—C₁₋₄alkyl andC₁₋₄alkyl-S(O)₂—C₁₋₄alkyl

In another aspect (FG5) the invention relates to compounds (I), wherein

ring system B and the p groups R¹⁰ together denote

In another aspect (FG6) the invention relates to compounds (I), wherein

ring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from amongC₁₋₄alkyl-O—C₂₋₄alkylene-NH, C₁₋₄alkyl-O—C₂₋₄alkylene-N(C₁₋₄alkyl),HO—C₂₋₄alkylene-N(C₁₋₄alkyl), HO—C₂₋₄alkylene-NH, 4-6 memberedheterocyclyl (optionally substituted by C₁₋₄alkyl, 3-6 memberedheterocyclyl, halogen, —OH, —CN, C₁₋₄alkoxy, —N(C₁₋₄alkyl)₂ orC₃₋₆cycloalkyl), (C₁₋₄alkyl)₂N—C₂₋₄alkylene-N(C₁₋₄alkyl),(C₁₋₄alkyl)₂N—C₂₋₄alkylene-NH, —N(C₁₋₄alkyl)₂, —NH(C₁₋₄alkyl),C₁₋₄alkyl-NH—C(O)— and (C₁₋₄alkyl)₂N—C(O).

In another aspect the invention relates to compounds (I), wherein

p has the value 1.

All the above-mentioned structural aspects A1 to A3, B1 to B3, C1 to C4,D1 to D4, CD1 to CD5, E1 to E3, F1 to F3, G1 to G3 and FG1 to FG6 arepreferred embodiments of the respective aspects A0, B0, C0, D0, CD0, E0,F0, G0 and FG0, wherein CD0 denotes the combination of C0 and D0 and FG0denotes the combination of F0 and G0. The structural aspects A0 to A3,B0 to B3, C0 to C4, D0 to D4, CD0 to CD5, E0 to E3, F0 to F3, G0 to G3and FG0 to FG6 with respect to different molecular parts of thecompounds (I) according to the invention may be permutated with oneanother as desired to form ABCDEFG combinations, thus obtainingpreferred compounds (I). Each ABCDEFG combination represents and definesindividual embodiments or generic partial amounts of compoundsA0B0C0D0E0F0G0 according to the invention. Every individual embodimentor partial quantity defined by this combination is expressly included inand a subject of the invention.

The present invention further relates to hydrates, solvates, polymorphs,metabolites, derivatives and prodrugs of compounds of general formula(I).

The present invention further relates to a pharmaceutically acceptablesalt of a compound of general formula (I) with anorganic or organicacids or bases.

In another aspect the invention relates to compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—as medicaments.

In another aspect the invention relates to compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—for use in a methodfor treatment of the human or animal body.

In another aspect the invention relates to compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—for use in thetreatment and/or prevention of cancer, infections, inflammations andautoimmune diseases.

In another aspect the invention relates to compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—for use in a methodfor treatment and/or prevention of cancer, infections, inflammations andautoimmune diseases in the human and animal body.

In another aspect the invention relates to the use of compounds ofgeneral formula (I)—or the pharmaceutically acceptable salts thereof—forpreparing a pharmaceutical composition for the treatment and/orprevention of cancer, infections, inflammations and autoimmune diseases.

In another aspect the invention relates to compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—for use in thetreatment and/or prevention of cancer.

In another aspect the invention relates to the use of compounds ofgeneral formula (I)—or the pharmaceutically acceptable salts thereof—forpreparing a pharmaceutical composition for the treatment and/orprevention of cancer.

In another aspect the invention relates to compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—for use in a methodfor treatment and/or prevention of cancer in the human or animal body.

In another aspect the invention relates to compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—for use in thetreatment and/or prevention of hepatocellular carcinomas (HCC),non-small cell lung cancer (NSCLC), breast cancer and prostate cancer.

In another aspect the invention relates to the use of compounds ofgeneral formula (I)—or the pharmaceutically acceptable salts thereof—forpreparing a pharmaceutical composition for the treatment and/orprevention of hepatocellular carcinomas (HCC), non-small cell lungcancer (NSCLC), breast cancer and prostate cancer.

In another aspect the invention relates to compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—for use in thetreatment and/or prevention of hepatocellular carcinomas (HCC) andnon-small cell lung cancer (NSCLC).

In another aspect the invention relates to the use of compounds ofgeneral formula (I)—or the pharmaceutically acceptable salts thereof—forpreparing a pharmaceutical composition for the treatment and/orprevention of hepatocellular carcinomas (HCC) and non-small cell lungcancer (NSCLC).

In another aspect the invention relates to a process for the treatmentand/or prevention of cancer comprising administering a therapeuticallyeffective amount of a compound of general formula (I)—or one of thepharmaceutically acceptable salts thereof—to a human being.

In another aspect the invention relates to a pharmaceutical preparationcontaining as active substance one or more compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—optionally incombination with conventional excipients and/or carriers.

In another aspect the invention relates to a pharmaceutical preparationcomprising a compound of general formula (I)—or one of thepharmaceutically acceptable salts thereof —and at least one othercytostatic or cytotoxic active substance, different from formula (I).

DEFINITIONS

Terms that are not specifically defined here have the meanings that areapparent to the skilled man in the light of the overall disclosure andthe context as a whole.

As used herein, the following definitions apply, unless statedotherwise:

The use of the prefix C_(x-y), wherein x and y each represent a naturalnumber (x<y), indicates that the chains or ring structure or combinationof chains and ring structure as a whole, specified and mentioned indirect association, may consist of a maximum of y and a minimum of xcarbon atoms.

The indication of the number of members in groups that contain one ormore heteroatom(s) (heteroalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl) relates to the total atomic number ofall the ring members or chain members or the total of all the ring andchain members.

Alkyl denotes monovalent, saturated hydrocarbon chains, which may bepresent in both straight-chain (unbranched) and branched form. If analkyl is substituted, the substitution may take place independently ofone another, by mono- or polysubstitution in each case, on all thehydrogen-carrying carbon atoms.

The term “C₁₋₅-alkyl” includes for example H₃C—, H₃C—CH₂—, H₃C—CH₂—CH₂—,H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—, H₃C—CH(CH₃)—CH₂—,H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—, H₃C—CH₂—CH₂—CH(CH₃)—,H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—, H₃C—CH₂—C(CH₃)₂—,H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— and H₃C—CH₂—CH(CH₂CH₃)—.

Further examples of alkyl are methyl (Me; —CH₃), ethyl (Et; —CH₂CH₃),1-propyl (n-propyl; n-Pr; —CH₂CH₂CH₃), 2-propyl (i-Pr; iso-propyl;—CH(CH₃)₂), 1-butyl (n-butyl; n-Bu; —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl(iso-butyl; i-Bu; —CH₂CH(CH₃)₂), 2-butyl (sec-butyl; sec-Bu;—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (tert-butyl; t-Bu; —C(CH₃)₃),1-pentyl (n-pentyl; —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃),3-pentyl (—CH(CH₂CH₃)₂), 3-methyl-1-butyl (iso-pentyl; —CH₂CH₂CH(CH₃)₂),2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂),2,2-dimethyl-1-propyl (neo-pentyl; —CH₂C(CH₃)₃), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (n-hexyl; —CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃), 2,3-dimethyl-1-butyl(—CH₂CH(CH₃)CH(CH₃)CH₃), 2,2-dimethyl-1-butyl (—CH₂C(CH₃)₂CH₂CH₃),3,3-dimethyl-1-butyl (—CH₂CH₂C(CH₃)₃), 2-methyl-1-pentyl(—CH₂CH(CH₃)CH₂CH₂CH₃), 3-methyl-1-pentyl (—CH₂CH₂CH(CH₃)CH₂CH₃),1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl,2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl,3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl,1-octyl (n-octyl), 1-nonyl (n-nonyl); 1-decyl (n-decyl) etc.

By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyletc. without any further definition are meant saturated hydrocarbongroups with the corresponding number of carbon atoms, wherein allisomeric forms are included.

The above definition for alkyl also applies if alkyl is a part ofanother group such as for example C_(x-y)-alkylamino orC_(x-y)-alkyloxy.

The term alkylene can also be derived from alkyl. Alkylene is bivalent,unlike alkyl, and requires two binding partners. Formally, the secondvalency is produced by removing a hydrogen atom in an alkyl.Corresponding groups are for example —CH₃ and —CH₂, —CH₂CH₃ and —CH₂CH₂or >CHCH₃ etc.

The term “C₁₋₄-alkylene” includes for example —(CH₂)—, —(CH₂—CH₂)—,—(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

Other examples of alkylene are methylene, ethylene, propylene,1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene,1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene,2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene,hexylene etc.

By the generic terms propylene, butylene, pentylene, hexylene etc.without any further definition are meant all the conceivable isomericforms with the corresponding number of carbon atoms, i.e. propyleneincludes 1-methylethylene and butylene includes 1-methylpropylene,2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.

The above definition for alkylene also applies if alkylene is part ofanother group such as for example in HO—C_(x-y)-alkylenamino orH₂N—C_(x-y)-alkylenoxy.

Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein atleast two adjacent carbon atoms are joined together by a C—C doublebond. If in an alkyl as hereinbefore defined having at least two carbonatoms, two hydrogen atoms on adjacent carbon atoms are formally removedand the free valencies are saturated to form a second bond, thecorresponding alkenyl is formed.

Examples of alkenyl are vinyl (ethenyl), prop-1-enyl, allyl(prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl,2-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl,1-methyl-prop-1-enyl, 1-methylidenepropyl, pent-1-enyl, pent-2-enyl,pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl,3-methyl-but-1-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl,hex-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl,2-methylidene-3-methylbutyl, 2,3-dimethyl-but-1-enyl, hexa-1,3-dienyl,hexa-1,4-dienyl, penta-1,4-dienyl, penta-1,3-dienyl, buta-1,3-dienyl,2,3-dimethylbuta-1,3-diene etc.

By the generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl,pentadienyl, hexa-dienyl, heptadienyl, octadienyl, nonadienyl,decadienyl etc. without any further definition are meant all theconceivable isomeric forms with the corresponding number of carbonatoms, i.e. propenyl includes prop-1-enyl and prop-2-enyl, butenylincludes but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl,1-methyl-prop-2-enyl etc.

Alkenyl may optionally be present in the cis or trans or E or Zorientation with regard to the double bond(s).

The above definition for alkenyl also applies when alkenyl is part ofanother group such as for example in C_(x-y)-alkenylamino orC_(x-y)-alkenyloxy.

Unlike alkylene, alkenylene consists of at least two carbon atoms,wherein at least two adjacent carbon atoms are joined together by a C—Cdouble bond. If in an alkylene as hereinbefore defined having at leasttwo carbon atoms, two hydrogen atoms at adjacent carbon atoms areformally removed and the free valencies are saturated to form a secondbond, the corresponding alkenylene is formed.

Examples of alkenylene are ethenylene, propenylene, 1-methylethenylene,butenylene, 1-methylpropenylene, 1,1-dimethylethenylene,1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene,2,2-dimethylpropenylene, 1,2-dimethylpropenylene,1,3-dimethylpropenylene, hexenylene etc.

By the generic terms propenylene, butenylene, pentenylene, hexenyleneetc. without any further definition are meant all the conceivableisomeric forms with the corresponding number of carbon atoms, i.e.propenylene includes 1-methylethenylene and butenylene includes1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and1,2-dimethylethenylene.

Alkenylene may optionally be present in the cis or trans or E or Zorientation with regard to the double bond(s).

The above definition for alkenylene also applies when alkenylene is apart of another group as in for example HO—C_(x-y)-alkenylenamino orH₂N—C_(x-y)-alkenylenoxy.

Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein atleast two adjacent carbon atoms are joined together by a C—C triplebond. If in an alkyl as hereinbefore defined having at least two carbonatoms, two hydrogen atoms in each case at adjacent carbon atoms areformally removed and the free valencies are saturated to form twofurther bonds, the corresponding alkynyl is formed.

Examples of alkynyl are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl,but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl,pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl,hex-3-ynyl, hex-4-ynyl, hex-5-ynyl etc.

By the generic terms propynyl, butynyl, pentynyl, hexynyl, heptynyl,octynyl, nonynyl, decynyl etc. without any further definition are meantall the conceivable isomeric forms with the corresponding number ofcarbon atoms, i.e. propynyl includes prop-1-ynyl and prop-2-ynyl,butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl,1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl, etc.

If a hydrocarbon chain carries both at least one double bond and also atleast one triple bond, by definition it belongs to the alkynyl subgroup.

The above definition for alkynyl also applies if alkynyl is part ofanother group, as in C_(x-y)-alkynylamino or C_(x-y)-alkynyloxy, forexample.

Unlike alkylene, alkynylene consists of at least two carbon atoms,wherein at least two adjacent carbon atoms are joined together by a C—Ctriple bond. If in an alkylene as hereinbefore defined having at leasttwo carbon atoms, two hydrogen atoms in each case at adjacent carbonatoms are formally removed and the free valencies are saturated to formtwo further bonds, the corresponding alkynylene is formed.

Examples of alkynylene are ethynylene, propynylene, 1-methylethynylene,butynylene, 1-methylpropynylene, 1,1-dimethylethynylene,1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene,2,2-dimethylpropynylene, 1,2-dimethylpropynylene,1,3-dimethylpropynylene, hexynylene etc.

By the generic terms propynylene, butynylene, pentynylene, hexynyleneetc. without any further definition are meant all the conceivableisomeric forms with the corresponding number of carbon atoms, i.e.propynylene includes 1-methylethynylene and butynylene includes1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and1,2-dimethylethynylene.

The above definition for alkynylene also applies if alkynylene is partof another group, as in HO—C_(x-y)-alkynyleneamino orH₂N—C_(x-y)-alkynyleneoxy, for example.

By heteroatoms are meant oxygen, nitrogen and sulphur atoms.

Haloalkyl (haloalkenyl, haloalkenyl) is derived from the previouslydefined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atomsof the hydrocarbon chain independently of one another by halogen atoms,which may be identical or different. If a haloalkyl (haloalkenyl,haloalkynyl) is to be further substituted, the substitutions may takeplace independently of one another, in the form of mono- orpolysubstitutions in each case, on all the hydrogen-carrying carbonatoms.

Examples of haloalkyl (haloalkenyl, haloalkynyl) are —CF₃, —CHF₂, —CH₂F,—CF₂CF₃, —CHFCF₃, —CH₂CF₃, —CF₂CH₃, —CHFCH₃, —CF₂CF₂CF₃, —CF₂CH₂CH₃,—CF═CF₂, —CCl═CH₂, —CBr═CH₂, —Cl═CH₂, —C≡C—CF₃, —CHFCH₂CH₃, —CHFCH₂CF₃etc.

From the previously defined haloalkyl (haloalkenyl, haloalkynyl) arealso derived the terms haloalkylene (haloalkenylene, haloalkynylene).Haloalkylene (haloalkenyl, haloalkynyl), unlike haloalkyl, is bivalentand requires two binding partners. Formally, the second valency isformed by removing a hydrogen atom from a haloalkyl.

Corresponding groups are for example —CH₂F and —CHF—, —CHFCH₂F and—CHFCHF— or >CFCH₂F etc.

The above definitions also apply if the corresponding halogen groups arepart of another group.

Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.

Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings,bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The systems aresaturated. In bicyclic hydrocarbon rings two rings are joined togetherso that they have at least two carbon atoms together. Inspiro-hydrocarbon rings a carbon atom (spiroatom) belongs to two ringstogether. If a cycloalkyl is to be substituted, the substitutions maytake place independently of one another, in the form of mono- orpolysubstitutions in each case, on all the hydrogen-carrying carbonatoms. Cycloalkyl itself may be linked as a substituent to the moleculevia every suitable position of the ring system.

Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl(octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthalene),bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl),bicyclo[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl etc.

The above definition for cycloalkyl also applies if cycloalkyl is partof another group as in C_(x-y)-cycloalkylamino or C_(x-y)-cycloalkyloxy,for example.

If the free valency of a cycloalkyl is saturated, then an alicyclicgroup is obtained.

The term cycloalkylene can thus be derived from the previously definedcycloalkyl. Cycloalkylene, unlike cycloalkyl, is bivalent and requirestwo binding partners. Formally, the second valency is obtained byremoving a hydrogen atom from a cycloalkyl.

Corresponding groups are for example

-   -   cyclohexyl and

The above definition for cycloalkylene also applies if cycloalkylene ispart of another group as in HO—C_(x-y)-cycloalkyleneamino orH₂N—C_(x-y)-cycloalkyleneoxy, for example.

Cycloalkenyl is also made up of the subgroups monocyclic hydrocarbonrings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. However,the systems are unsaturated, i.e. there is at least one C—C double bondbut no aromatic system. If in a cycloalkyl as hereinbefore defined twohydrogen atoms at adjacent cyclic carbon atoms are formally removed andthe free valencies are saturated to form a second bond, thecorresponding cycloalkenyl is obtained. If a cycloalkenyl is to besubstituted, the substitutions may take place independently of oneanother, in the form of mono- or polysubstitutions in each case, on allthe hydrogen-carrying carbon atoms. Cycloalkenyl itself may be linked asa substituent to the molecule via every suitable position of the ringsystem.

Examples of cycloalkenyl are cycloprop-1-enyl, cycloprop-2-enyl,cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl,cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl,cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl,cyclobuta-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,3-dienyl,cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohexa-1,5-dienyl,cyclohexa-2,4-dienyl, cyclohexa-1,4-dienyl, cyclohexa-2,5-dienyl,bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl),bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4.5]dec-2-ene etc.

The above definition for cycloalkenyl also applies when cycloalkenyl ispart of another group as in C_(x-y)-cycloalkenylamino orC_(x-y)-cycloalkenyloxy, for example.

If the free valency of a cycloalkenyl is saturated, then an unsaturatedalicyclic group is obtained.

The term cycloalkenylene can thus be derived from the previously definedcycloalkenyl.

Cycloalkenylene, unlike cycloalkenyl, is bivalent and requires twobinding partners. Formally the second valency is obtained by removing ahydrogen atom from a cycloalkenyl. Corresponding groups are for example

cyclopentenyl and

etc.

The above definition for cycloalkenylene also applies whencycloalkenylene is part of another group as inHO—C_(x-y)-cycloalkenyleneamino or H₂N—C_(x-y)-cycloalkenyleneoxy, forexample.

Aryl denotes a mono-, bi- or tricyclic group with at least one aromaticcarbocycle. Preferably it denotes a monocyclic group with six carbonatoms (phenyl) or a bicyclic group with nine or ten carbon atoms (twosix-membered rings or one six-membered ring with a five-membered ring),wherein the second ring may also be aromatic or, however, may also besaturated or partially saturated. If an aryl is to be substituted, thesubstitutions may take place independently of one another, in the formof mono- or polysubstitutions in each case, on all the hydrogen-carryingcarbon atoms. Aryl itself may be linked as a substituent to the moleculevia every suitable position of the ring system.

Examples of aryl are phenyl, naphthyl, indanyl (2,3-dihydroindenyl),indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl(1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl(1,2-dihydronaphthyl), fluorenyl etc.

The above definition of aryl also applies when aryl is part of anothergroup as in arylamino or aryloxy, for example.

If the free valency of an aryl is saturated, then an aromatic group isobtained.

The term arylene can also be derived from the previously defined aryl.Arylene, unlike aryl, is bivalent and requires two binding partners.Formally, the second valency is formed by removing a hydrogen atom froman aryl. Corresponding groups are e.g.

-   -   phenyl and

-   -   naphthyl and

etc.

The above definition for arylene also applies when arylene is part ofanother group as in HO-aryleneamino or H₂N-aryleneoxy for example.

Heterocvclyl denotes ring systems, which are derived from the previouslydefined cycloalkyl, cycloalkenyl and aryl by replacing one or more ofthe groups —CH₂— independently of one another in the hydrocarbon ringsby the groups —O—, —S— or —NH— or by replacing one or more of the groups═CH— by the group ═N—, wherein a total of not more than five heteroatomsmay be present, at least one carbon atom may be present between twooxygen atoms and between two sulphur atoms or between one oxygen and toone sulphur atom and the ring as a whole must have chemical stability.Heteroatoms may optionally be present in all the possible oxidationstages (sulphur→sulphoxide —SO—, sulphone —SO₂—; nitrogen→N-oxide). In aheterocyclyl there is no heteroaromatic ring, i.e. no heteratom is partof an aromatic system.

A direct result of the derivation from cycloalkyl, cycloalkenyl and arylis that heterocyclyl is made up of the subgroups monocyclic heterorings,bicyclic heterorings, tricyclic heterorings and spiro-heterorings, whichmay be present in saturated or unsaturated form. By unsaturated is meantthat there is at least one double bond in the ring system in question,but no heteroaromatic system is formed. In bicyclic heterorings tworings are linked together so that they have at least two (hetero)atomsin common. In spiro-heterorings a carbon atom (spiroatom) belongs to tworings together. If a heterocyclyl is substituted, the substitutions maytake place independently of one another, in the form of mono- orpolysubstitutions in each case, on all the hydrogen-carrying carbonand/or nitrogen atoms. Heterocyclyl itself may be linked as asubstituent to the molecule via every suitable position of the ringsystem.

Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl,1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl,homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl,thiomorpholinyl-5-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxolanyl,tetrahydropyranyl, tetrahydrothiopyranyl, [1,4]-oxazepanyl,tetrahydrothienyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl,dihydro-pyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl-5-oxide, tetrahydrothienyl-S,S-dioxide,homothiomorpholinyl-5-oxide, 2,3-dihydroazet, 2H-pyrrolyl, 4H-pyranyl,1,4-dihydropyridinyl, 8-azabicyclo[3.2.1]octyl,8-azabicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1]octyl,2,5-diaza-bicyclo-[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl,3,8-diaza-bicyclo[3.2.1]octyl, 3,9-diaza-bicyclo[4.2.1]nonyl,2,6-diaza-bicyclo[3.2.2]nonyl, 1,4-dioxa-spiro[4.5]decyl,1-oxa-3,8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]heptyl,2,7-diaza-spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]octyl,3,9-diaza-spiro[5.5]undecyl, 2,8-diaza-spiro[4.5]decyl etc.

Further examples are the structures illustrated below, which may beattached via each hydrogen-carrying atom (exchanged for hydrogen):

The above definition of heterocyclyl also applies if heterocyclyl ispart of another group as in heterocyclylamino or heterocyclyloxy forexample.

If the free valency of a heterocyclyl is saturated, then a heterocyclicgroup is obtained.

The term heterocyclylene is also derived from the previously definedheterocyclyl. Heterocyclylene, unlike heterocyclyl, is bivalent andrequires two binding partners. Formally, the second valency is obtainedby removing a hydrogen atom from a heterocyclyl. Corresponding groupsare for example

-   -   piperidinyl and

2,3-dihydro-1H-pyrrolyl and

etc.

The above definition of heterocyclylene also applies if heterocyclyleneis part of another group as in HO-heterocyclyleneamino orH₂N-heterocyclyleneoxy for example.

Heteroaryl denotes monocyclic heteroaromatic rings or polycyclic ringswith at least one heteroaromatic ring, which compared with thecorresponding aryl or cycloalkyl (cycloalkenyl) contain, instead of oneor more carbon atoms, one or more identical or different heteroatoms,selected independently of one another from among nitrogen, sulphur andoxygen, wherein the resulting group must be chemically stable. Theprerequisite for the presence of heteroaryl is a heteroatom and aheteroaromatic system. If a heteroaryl is to be substituted, thesubstitutions may take place independently of one another, in the formof mono- or polysubstitutions in each case, on all the hydrogen-carryingcarbon and/or nitrogen atoms. Heteroaryl itself may be linked as asubstituent to the molecule via every suitable position of the ringsystem, both carbon and nitrogen. Examples of heteroaryl are furyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-N-oxide,pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide,pyrazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide,oxazolyl-N-oxide, thiazolyl-N-oxide, oxadiazolyl-N-oxide,thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, indolyl,isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl,isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl,quinazolinyl, benzotriazinyl, indolizinyl, oxazolopyridyl,imidazopyridyl, naphthyridinyl, benzoxazolyl, pyridopyridyl, purinyl,pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl,quinolinyl-N-oxide, indolyl-N-oxide, isoquinolyl-N-oxide,quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide,indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide,benzimidazolyl-N-oxide etc.

Further examples are the structures illustrated below, which may beattached via each hydrogen-carrying atom (exchanged for hydrogen):

The above definition of heteroaryl also applies when heteroaryl is partof another group as in heteroarylamino or heteroaryloxy, for example.

If the free valency of a heteroaryl is saturated, a heteroaromatic croupis obtained.

The term heteroarylene can therefore be derived from the previouslydefined heteroaryl. Heteroarylene, unlike heteroaryl, is bivalent andrequires two binding partners. Formally, the second valency is obtainedby removing a hydrogen atom from a heteroaryl. Corresponding groups arefor example

-   -   pyrrolyl and etc.

The above definition of heteroarylene also applies when heteroarylene ispart of another group as in HO-heteroaryleneamino orH₂N-heteroaryleneoxy, for example.

The above-mentioned bivalent groups (alkylene, alkenylene, alkynyleneetc.) may also be a part of composite groups (e.g. H₂N—C₁₋₄alkylene orHO—C₁₋₄alkylene-). In this case one of the valencies is saturated by theattached group (in this case: —NH₂, —OH), so that a composite group ofthis kind in this nomenclature amounts in total to only a monovalentsubstituent.

By substituted is meant that a hydrogen atom which is bound directly tothe atom under consideration, is replaced by another atom or anothergroup of atoms (substituent). Depending on the starting conditions(number of hydrogen atoms) mono- or polysubstitution may take place onone atom. Substitution with a particular substituent is only possible ifthe permitted valencies of the substituent and of the atom that is to besubstituted correspond to one another and the substitution leads to astable compound (i.e. to a compound which is not convertedspontaneously, e.g. by rearrangement, cyclisation or elimination).

Bivalent substituents such as ═S, ═NR, ═NOR, ═NNRR, ═NN(R)C(O)NRR, ═N₂or the like, may only be substituents at carbon atoms, wherein thebivalent substituent ═O may also be a substituent at sulphur. Generally,substitution may be carried out by a bivalent substituent only at ringsystems and requires replacement by two geminal hydrogen atoms, i.e.hydrogen atoms that are bound to the same carbon atom that is saturatedprior to the substitution. Substitution by a bivalent substituent istherefore only possible at the group —CH_(2—) or sulphur atoms of a ringsystem.

Stereochemistry/Solvates/Hydrates:

Unless stated otherwise a structural formula given in the description orin the claims or a chemical name refers to the corresponding compounditself, but also encompasses the tautomers, stereoisomers, optical andgeometric isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.),racemates, mixtures of separate enantiomers in any desired combinations,mixtures of diastereomers, mixtures of the forms mentioned hereinbefore(if such forms exist) as well as salts, particularly pharmaceuticallyacceptable salts thereof. The compounds and salts according to theinvention may be present in solvated form (e.g. with pharmaceuticallyacceptable solvents such as e.g. water, ethanol etc.) or in unsolvatedform. Generally, for the purposes of the present invention the solvatedforms, e.g. hydrates, are to be regarded as of equal value to theunsolvated forms.

Salts:

The term “pharmaceutically acceptable” is used herein to denotecompounds, materials, compositions and/or formulations which aresuitable, according to generally recognised medical opinion, for use inconjunction with human and/or animal tissue and do not have or give riseto any excessive toxicity, irritation or immune response or lead toother problems or complications, i.e. correspond overall to anacceptable risk/benefit ratio.

The term “pharmaceutically acceptable salts” relates to derivatives ofthe chemical compounds disclosed in which the parent compound ismodified by the addition of acid or base. Examples of pharmaceuticallyacceptable salts include (without being restricted thereto) salts ofmineral or organic acids in relation to basic functional groups such asfor example amines, alkali metal or organic salts of acid functionalgroups such as for example carboxylic acids, etc. These salts include inparticular acetate, ascorbate, benzenesulphonate, benzoate, besylate,bicarbonate, bitartrate, bromide/hydrobromide, Ca-edetate/edetate,camsylate, carbonate, chloride/hydrochloride, citrate, edisylate, ethanedisulphonate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycolate, glycollylarsnilate, hexylresorcinate, hydrabamine,hydroxymaleate, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, malate, maleate, mandelate, methanesulphonate, mesylate,methylbromide, methylnitrate, methylsulphate, mucate, napsylate,nitrate, oxalate, pamoate, pantothenate, phenyl acetate,phosphate/diphosphate, polygalacturonate, propionate, salicylate,stearate, subacetate, succinate, sulphamide, sulphate, tannate,tartrate, teoclate, toluenesulphonate, triethiodide, ammonium,benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine,meglumin and procaine. Other pharmaceutically acceptable salts may beformed with cations of metals such as aluminium, calcium, lithium,magnesium, potassium, sodium, zinc, etc. (cf. also Pharmaceutical salts,Birge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention may beprepared starting from the parent compound which carries a basic oracidic functionality, by conventional chemical methods. Generally, suchsalts may be synthesised by reacting the free acid or base form of thesecompounds with a sufficient amount of the corresponding base or acid inwater or an organic solvent such as for example ether, ethyl acetate,ethanol, isopropanol, acetonitrile (or mixtures thereof).

Salts of acids other than those mentioned above, which are useful forexample for purifying or isolating the compounds from the reactionmixtures (e.g. trifluoroacetates), are also to be regarded as part ofthe invention.

In a representation such as for example

the letter A has the function of a ring designation in order to make iteasier, for example, to indicate the attachment of the ring in questionto other rings.

For bivalent groups in which it is crucial to determine which adjacentgroups they bind and with which valency, the corresponding bindingpartners are indicated in brackets, where necessary for clarificationpurposes, as in the following representations:

or (R²)—C(O)NH— or (R²)—NHC(O)—;

Groups or substituents are frequently selected from among a number ofalternative groups/substituents with a corresponding group designation(e.g. R^(a), R^(b) etc). If such a group is used repeatedly to define acompound according to the invention in different molecular parts, itmust always be borne in mind that the various uses are to be regarded astotally independent of one another.

By a therapeutically effective amount for the purposes of this inventionis meant a quantity of substance that is capable of obviating symptomsof illness or of preventing or alleviating these symptoms, or whichprolong the survival of a treated patient.

LIST OF ABBREVIATIONS

aa amino acid Ac acetyl equiv. equivalent(s) Ar (hetero)aryl ATPadenosine triphosphate Boc tert-butyloxycarbonyl BSA bovine serumalbumin Bu butyl d day(s) TLC thin layer chromatography DCCdicyclohexylcarbodiimide DCM dichloromethane DEA diethylamine DICdiisopropylcarbodiimide DIPEA N-ethyl-N,N-diisopropylamine (HÜNIG-base)DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DMFN,N-dimethylformamide DMF-DMA N,N-dimethylformamide-dimethylacetal DMSOdimethylsulphoxide dppf 1,1′-bis(diphenylphosphino)ferrocene EDCN-(3-dimethylaminopropyl)-N4-ethylcarbodiimide hydrochloride ESIelectron spray ionization Et ethyl EtOH ethanol h hour(s) HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl- uroniumhexafluorophosphate HCl hydrochloric acid het hetero HPLC highperformance liquid chromatography HÜNIG baseN-ethyl-N,N-diisopropylamine i iso iPr₂NEt diisopropylethylamine (HÜNIGbase) iPrOH isopropanol cat. catalyst, catalytic conc. concentrated LCliquid chromatography sin. solution M molar Me methyl MeOH methanol minminute(s) mL millilitres MPLC medium pressure liquid chromatography MSmass spectrometry MW microwave N normal NMP N-methylpyrrolidinone PBSphosphate-buffered saline Pd-dppf 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)- dichloride dichloromethane Ph phenyl PK pharmacokineticsPr propyl R_(f) (Rf) retention factor RP reversed phase RT ambienttemperature s second(s) TBTUO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium tetrafluoroborateTEA triethylamine tert tertiary Tf triflate TFA trifluoroacetic acid THFtetrahydrofuran TMS trimethylsilyl Tos tosyl t_(Ret.) retention time(HPLC) TRIS tris(hydroxymethyl)-aminomethane UV ultraviolet

Features and advantages of the present invention will become apparentfrom the following detailed Examples, which illustrate the fundamentalsof the invention by way of example, without restricting its scope:

Preparation of the Compounds According to the Invention General

Unless stated otherwise, all the reactions are carried out incommercially obtainable apparatus using methods that are commonly usedin chemical laboratories. Starting materials that are sensitive to airand/or moisture are stored under protective gas and correspondingreactions and manipulations therewith are carried out under protectivegas (nitrogen or argon).

The compounds are named according to the Beilstein rules using theAutonom software (Beilstein). If a compound is to be represented both bya structural formula and by its nomenclature, in the event of a conflictthe structural formula is decisive.

Microwave reactions are carried out in an initiator/reactor made byBiotage or Synthos 3000 and Monowave 300 made by the company Anton Paarin sealed containers (preferably 2, 5 or 20 mL), preferably withstirring.

Chromatography

Thin layer chromatography is carried out on ready-made TLC plates ofsilica gel 60 on glass (with fluorescence indicator F-254) made byMerck.

The preparative high pressure chromatography (HPLC) of the examplecompounds according to the invention is carried out with columns made byWaters (names: Sunfire C18, 5 μm, 30×100 mm Part. No. 186002572;X-Bridge C18, 5 μm, 30×100 mm Part. No. 186002982).

The compounds are eluted using either different gradients ofH₂O/acetonitrile or H₂O/MeOH, wherein preferably 0.1% HCOOH is added tothe water (acid conditions). For chromatography under basic conditionsH₂O/acetonitrile gradients are also used, and the water is made basicaccording to the following recipe: 5 mL of an ammonium hydrogencarbonate solution (158 g to 1 L H₂O) and 2 mL ammonia (7M in MeOH) aremade up to 1 L with H₂O.

The normal-phase preparative high pressure chromatography (HPLC) of theexample compounds according to the invention is carried out with columnsmade by Macherey & Nagel (name: Nucleosil, 50-7, 40×250 mm) andVDSoptilab (name: Kromasil 100 NH₂, 10 μM, 50×250 mm). The compounds areeluted using different gradients of DCM/MeOH, with 0.1% NH₃ added to theMeOH.

The analytical HPLC (reaction monitoring) of intermediate compounds iscarried out with columns made by Agilent, Waters and Phenomenex. Theanalytical equipment is also provided with a mass detector in each case.

HPLC Mass Spectroscopy/UV Spectrometry

The retention times/MS-ESL for characterising the example compoundsaccording to the invention are produced using an HPLC-MS apparatus (highperformance liquid chromatography with mass detector) made by Agilent.Compounds that elute at the injection peak are given the retention timet_(Ret.)=0.00.

HPLC-Methods Preparative

prep. HPLC1

-   -   HPLC: 333 and 334 Pumps    -   Column: Waters X-Bridge C18, 5 μm, 30×100 mm, Part. No.        186002982    -   Eluant: A: 10 mM NH₄HCO₃ in H₂O; B: acetonitrile (HPLC grade)    -   Detection: UV/Vis-155    -   Flow: 50 mL/min    -   Gradient: 0.00 min: 5% B        -   3.00-15.00 min: variable (see individual methods)        -   15.00-17.00 min: 100% B            prep. HPLC2    -   HPLC: 333 and 334 Pumps    -   Column: Waters Sunfire C18, 5 μm, 30×100 mm, Part. No. 186002572    -   Eluant: A: H₂O+0.2% HCOOH; B: acetonitrile (HPLC grade)+0.2%        HCOOH    -   Detection: UV/Vis-155    -   Flow: 50 mL/min    -   Gradient: 0.00 min: 5% B        -   3.00-15.00 min: variable (see individual methods)    -   15.00-17.00 min: 100% B

Analytical Method A

HPLC Agilent 1100 Series MS 1100 Series LC/MSD SL (MM-ES + APCI, + 3000V, Quadrupol, G1956B) MSD signal settings Scan pos 120−750 columnWaters, XBridge, C18, 3.5 μm, 135 Å, 30 × 2.1 mm column, Part. No:186003020 eluant A: 5 mM NH₄HCO₃/20 mM NH₃ (pH = 9.5) B: acetonitrile(HPLC grade) detection signal UV 254/214 nm (bandwidth 8, reference off)spectrum range: 190-400 nm; step: 2.0 nm peak width >00025 min (0.05 s)injection 2 μL standard injection flow 1.0 mL/min column temperature 35°C. gradient 0.0-1.0 min 15% → 95% B 1.0-1.6 min 95% B 1.6-1.7 min 95% →15% B 1.7-2.3 min 15% B

Method B

HPLC Agilent 1100 Series MS 1100 Series LC/MSD SL (MM-ES + APCI, + 3000V, Quadrupol, G1956B) MSD signal settings Scan pos 120−750 columnWaters, XBridge, C18, 3.5 μm, 135 Å, 30 × 2.1 mm column, Part. No.:186003020 eluant A: 5 mM NH₄HCO₃/20 mM NH₃ (pH = 9.5) B: MeOH (HPLCgrade) detection signal UV 254/214 nm (bandwidth 8, reference off)spectrum range: 190-400 nm; step: 2.0 nm peak width >00025 min (0.05 s)injection 2 μL standard injection flow 1.0 mL/min column temperature 40°C. gradient 0.0-1.0 min 20% → 95% B 1.0-2.0 min 95% B 2.0-2.1 min 95% →20% B 2.1-2.3 min 20% B

Method C

HPLC Agilent 1100 Series MS 1200 Series LC/MSD (API-ES + 3000 V,Quadrupol, G6140A) MSD signal settings Scan pos 150−750 column Agilent.Zorbax SB, C8, 3.5 μm, 80 Å, 50 × 2.1 mm column, Part. No.: 871700-906eluant A: water + 0.11% formic acid B: acetonitrile (HPLC grade) + 0.1%formic acid detection signal UV 254/214/230 nm (bandwidth 8, referenceoff) spectrum range: 190-450 nm; step: 4.0 nm peak width >0.01 min (0.2s) injection 1.5 μL standard injection flow 1.1 mL/min columntemperature 45° C. gradient 0.0-1.75 min 15% → 95% B 1.75-1.9 min 95% B1.9-1.92 min 95% → 15% B 1.92-2.1 min 15% B

Method D

HPLC Agilent 1100 Series MS 1100 Series LC/MSD SL (MM-ES + APCI, + 2500V, Quadrupol, G1956B) MSD signal settings Scan pos 70 − 500 columnAgilent Zorbax SB, C8, 3.5 μm, 80 Å, 50 × 2.1 mm column, Part. No.:871700-906 eluant A: water + 0.11% formic acid B: MeOH (HPLC grade)detection signal UV 254/214/230 nm (bandwidth 8, reference off) spectrumrange: 190-450 nm; step: 4.0 nm peak width >0.01 min (0.2 s) injection1.5 μL standard injection flow 1.0 mL/min column temperature 45° C.gradient 0.0-1.5 min 20% → 95% B 1.5-2.1 min 95% B 2.1-2.2 min 95% → 20%B 2.2-2.4 min 20% B

Method E

HPLC Agilent 1100 Series MS 1100 Series LC/MSD SL (MM-ES + APCI, + 3000V, Quadrupol, G1956B) MSD signal settings Scan pos 100−750 columnWaters, XBridge, C18, 3.5 μm, 135 Å, 30 × 2.1 mm column, Part. No.:186003020 eluant A: 5 mM NH₄HCO₃/20 mM NH₃ (pH = 9.5) B: acetonitrile(HPLC grade) detection signal UV 254/214 nm (bandwidth 8, reference off)spectrum range: 190-400 nm; step: 2.0 nm peak width >0005 min (0.1 s)injection 2 μL standard injection flow 1.0 mL/min column temperature 35°C. gradient 0.0-1.0 min 15% → 95% B 1.0-1.6 min 95% B 1.6-1.7 min 95% →15% B 1.7-2.3 min 15% B

Method F

HPLC Agilent 1100 Series MS 1200 Series LC/MSD (API-ES + 2500 V,Quadrupol, G6140A) MSD signal settings Scan pos 75−500 column AgilentZorbax SB, C8, 3.5 μm, 80 Å, 50 × 2.1 mm column, Part. No.: 871700-906eluant A: water + 0.11% formic acid B: acetonitrile (HPLC grade) +0.1%formic acid detection signal UV 254/214/230 nm (bandwidth 8, referenceoff) spectrum range: 190-450 nm; step: 4.0 nm peak width >0.01 min (0.2s) injection 1.5 μL standard injection flow 1.1 mL/min columntemperature 45° C. gradient 0.0-1.75 min 15% → 95% B 1.75-1.9 min 95% B1.9-1.92 min 95% → 15% B 1.92-2.1 min 15% B

Method G

HPLC Agilent 1100 Series MS 1100 Series LC/MSD (API-ES +/− 3000 V,Quadrupol, G1946D) MSD signal settings Scan pos 120−900, Scan neg120−900 column phenomenex; Part. No. 00M-4439-BO-CE; Gemini 3 μm, C18,110 Å; 20 × 2.0 mm column eluant A: 5 mM NH₄HCO₃/20 mM NH₃ (pH = 9.5) B:acetonitrile (HPLC grade) detection signal UV 254 nm (bandwidth 1,reference off) spectrum range: 250-400 nm; step: 1 nm peak width <0.01min (0.1 s) injection 10 μL standard injection flow 1.0 mL/min columntemperature 40° C. gradient 0.0-2.5 min  5% → 95% B 2.5-2.8 min 95% B2.8-3.1 min 95% → 5% B

Method H

HPLC Agilent G1312A binary pump with Waters 2996 PDA detector MS WatersZQ MSD Signal Settings Scan pos 150−850 column Waters; Part. No.186001295; Atlantis dC18, 2.1 × 100.0 mm, 3 μm column eluant A: 0.1%formic acid in water B: 0.1% formic acid in acetonitrile (HPLC grade)detection signal UV 215 nm spectrum range: 200-420 nm; step: 1 nminjection 3 μL flow 0.6 mL/min column temperature 40° C. gradient 0.0min  5% B 0.0-5.0 min  5% → 100% B 5.0-5.4 min 100% B 5.4-5.42 min 100%→ 5% B 5.42-7.0 min  5% B

Method I

HPLC Shimadzu Prominence Series MS Shimadzu LCMS-2010EV system MSDSignal Settings Scan pos 100-1000 column Waters; Part. No. 186001291;Atlantis dC18, 2.1 × 50.0 mm, 3 μm column eluant A: 0.1% formic acid inwater B: 0.1% formic acid in acetonitrile (HPLC grade) detection signalUV 215 nm spectrum range: 210-420 nm; step: 1 nm injection   3 μL flow1.0 mL/min column temperature 40° C. gradient 0.0 min  5% B 0.0-2.5 min 5% → 100% B 2.5-2.7 min 100% B 2.7-2.71 min 100% → 5% B 2.71-3.50 min 5% B

Method J

HPLC Agilent G1312A binary pump with Waters 2996 PDA detector MS WatersLCT (MS5) or Waters ZQ (MS10) MSD Signal Settings Scan pos 150-850column Phenomenex; Part No. 00D-4453-B0; Gemini C18, 2.0 × 100.0 mm, 3μm column eluant A: 2 mM NH₄HCO₃ buffered to pH = 10 B: acetonitrile(HPLC grade) detection signal UV 215 nm spectrum range: 200-420 nm;step: 1 nm injection   3 μL flow 0.5 mL/min column temperature 50° C.gradient 0.0 min   5% B 0.0-5.5 min  5% → 100% B 5.5-5.9 min 100% B5.9-5.92 min 100% → 5% B 5.92-9.0 min   5% B

Method K

HPLC Shimadzu Prominence Series MS Shimadzu LCMS-2010EV System MSDSignal Settings Scan pos 100-1000 column Waters; Part. No. 186001287;Atlantis dC18, 2.1 × 30.0 mm, 3 μm column eluant A: 0.1% formic acid inwater B: 0.1% formic acid in acetonitrile (HPLC grade) detection signalUV 215 nm spectrum range: 220-420 nm; step: 1 nm injection   3 μL flow1.0 mL/min column temperature 40° C. gradient 0.0 min   5% B 0.0-1.5 min 5% → 100% B 1.5-1.6 min 100% B 1.6-1.61 min 100% → 5% B

Method L

HPLC Agilent 1100 Series MS 1100 Series LC/MSD SL (MM-ES + APCI, +3000V, Quadrupol, G1956B) MSD Signal Settings Scan pos 120-750 columnWaters, XBridge, C18, 5.0 pm, 50 × 2.1 mm column, Part. No.: 186003108eluant A: 5 mM NH₄HCO₃/20 mM NH₃ (pH = 9.5) B: acetonitrile (HPLC grade)detection signal UV 254/214 nm (bandwidth 8, reference off) spectrumrange: 190-400 nm; step: 2.0 nm peak width  >00025 min (0.05 s)injection      2 μL standard injection flow     1.2 mL/min columntemperature 35° C. gradient 0.0-1.25 min  5% → 100% B 1.25-2.0 min 100%B 2.0-3.1 min 100% → 5% B

Method M

HPLC Agilent 1100 Series MS Agilent LC/MSD SL MSD Signal Settings MS:Positive and negative Mass range: 120-900 m/z column Waters, XbridgeC18 ™, 2.5 μm, 2.1 × 20 mm, Part. No.186003201 eluant A: 20 mMNH₄HCO₃/NH₃ pH 9 B: acetonitrile (HPLC grade) detection signal UV,bandwidth 170 nm, reference off spectrum range: 230-400 nm; step: 1.0 nmpeak width <0.01 min injection     5 μL standard injection flow    1.0mL/min column temperature 60° C. gradient 0.0 min 10% B 0.0-1.5 min 10%→ 95% B 1.5-2.0 min 95% B 2.0-2.1 min 95% → 10% B

Method N

HPLC Agilent 1100 Series MS 1200 Series LC/MSD (API-ES +/− 3000 V,Quadrupol, G6130A) MSD Signal Settings Scan pos 105-1200, Scan neg.105-1200 column Waters, XBridge, C18, 5 μm, 135 Å, 30 × 2.1 mm column,Part. No.: 186003108 eluant A: 5 mM NH₄HCO₃/19 mM NH₃ (pH = 9.5) B:acetonitrile (HPLC grade) detection signal UV 254/230 nm (bandwidth 8,reference off) spectrum range: 190-450 nm; step: 4.0 nm peak width >0.03min (0.5 s) injection     2 μL standard injection flow    1.2 mL/mincolumn temperature 35° C. gradient 0.0-1.25 min  5% → 95% B 1.25-2.0 min95% B 2.0-2.01 min 95% → 5% B 2.01-3.0 min  5% B

Method O

HPLC Agilent 1200 Series MS 1100 Series LC/MSD (API-ES +/− 3000 V,Quadrupol, G1946D) MSD Signal Settings Scan pos 105-1200, Scan neg.105-1200 column Waters, XBridge, C18, 5 μm, 135 Å, 30 × 2.1 mm column,Part. No.: 186003108 eluant A: 5 mM NH₄HCO₃/19 mM NH₃ (pH = 9.5) B:acetonitrile (HPLC grade) detection signal UV 254/230 nm (bandwidth 8,reference off) spectrum range: 190-450 nm; step: 4.0 nm peak width >0.03min (0.5 s) injection     2 μL standard injection flow    1.2 mL/mincolumn temperature 35° C. gradient 0.0-1.25 min  5% → 100% B 1.25-2.0min 100% B 2.0-2.01 min 100% → 5% B 2.01-3.0 min  5% B

Method P

HPLC Agilent 1100 Series MS Agilent LC/MSD SL MSD Signal Settings MS:Positive and negative Mass range: 120-800 m/z column Waters, XBridge ™C18, 2.5 μm, 2.1 × 20 mm; Part. No. 186003201 eluant A: 0.1% NH₃ (pH =9-10) B: acetonitrile (HPLC grade) detection signal UV, bandwidth 170nm, reference off spectrum range: 230-400 nm; step: 2.0 nm peak width<0.01 min injection     5 μL standard injection flow    1.0 mL/mincolumn temperature 60° C. gradient 0.0  5% B 0.0-2.5 min  5% → 95% B2.5-2.8 min 95% B 2.81-3.1 min  5% → 95% B

Method Q

HPLC Agilent 1100 column AD-H (Messrs. Chiralcel; 4.6 × 150 mm) eluantMeOH + 0.1% DEA flow 0.7 mL/min column temperature 40° C. gradientisocratic

Method R

HPLC Agilent 1100 column LUX2 (Messrs. Phenomenex; 4.6 × 150 mm) eluantMeOH + 0.1% DEA flow 0.7 mL/min column temperature 40° C. gradientisocratic

The compounds according to the invention are prepared by the methods ofsynthesis described hereinafter, in which the substituents of thegeneral formulae have the meanings given hereinbefore. These methods areintended as an illustration of the invention, without restricting itssubject matter and the scope of the compounds claimed to these examples.Where the preparation of starting compounds is not described, they arecommercially obtainable or may be prepared analogously to knowncompounds or methods described herein. Substances described in theliterature are prepared according to the published methods of synthesis.

General Formula Scheme and Summary of the Synthesis Route

In principle, 2,4-diaminopyrimidine derivatives may be prepared fromcorrespondingly substituted chloropyrimidines. The reactivity of thesechloropyrimidines is controlled by the substituent in position 5, withthe result that different synthesis strategies have to be adopteddepending on the nature of this substituent.

For all the substituents with the exception of the trifluoromethyl group(—CF₃) functionalisation may be carried out in the 4 position as thefirst step. By reacting the 2,4-dichloro compound A1 with thecorresponding amine R⁴—NH₂ the intermediate B is obtained, which may inturn be converted into the 2,4-diaminopyrimidine C1 by reaction with a(hetero)aromatic amine R²—NH₂.

Alternatively, 2,4-diaminopyrimidines C1 may also be prepared startingfrom 2-methylsulphanyl-3H-pyrimidin-4-one by reacting with a(hetero)aromatic amine R²—NH₂ followed by halogenation in position 5 viathe intermediates D and E. The cyclic amide E may be reacted withphosphoryl chloride to obtain the 4-chloropyrimidine F1, which in turnleads to C1 by reaction with a correspondingly configured amine R⁴—NH₂.

2,4-Dichloropyrimidine A2 substituted in position 5 by a trifluoromethylgroup may be reacted in the presence of zinc chloride with a(hetero)aromatic amine R²—NH₂ and thus yields the 4-chloropyrimidine F2,which may in turn be reacted with amines R⁴—NH₂ and converted into the2,4-diaminopyrimidine C2.

The 2,4-diaminopyrimidines C1 and C2 may on the one hand be endcompounds (I) according to the invention or on the other hand may beprepared using correspondingly protected amines in positions 2 and 4,deprotected by conventional methods and then converted into the actualend compounds (I) designated G1 or G2 by one or more derivatisationsteps such as e.g. amide formation, alkylation or amination reactions.Instead of protected amines it is also possible to use synthesiscomponents which can be directly functionalised or derivatised withoutrecourse to protective groups.

In end compounds (I) according to the invention the group R² correspondsto a grouping having the structure

and the group R⁴ to a grouping having the structure

1. Preparation of the Oxindole Components (=amine R⁴—NH₂)

1.1 Preparation of 4-cyanooxindole (Method A)

4-bromoxindole (2.0 g, 9.43 mmol), zinc cyanide (680 mg, 5.68 mmol),tris(bisbenzylideneacetone)dipalladium (250 mg, 0.27 mmol) and1,1′-diphenylphosphineferrocene (300 mg, 0.54 mmol) are stirred inanhydrous DMF (10 mL) for 2 h at 140° C. under argon. The reactionmixture is cooled and poured onto 30% aqueous ethanol. The precipitateis filtered off, digested with water and EtOH and dried.

1.2 Preparation of 4-cyano-3,3-dimethyloxindole (Method B)

4-cyanooxindole (6.80 g, 43.0 mmol) in anhydrous THF (40 mL) is combinedwith sodium hydride (60% dispersion in white oil, 7.0 g, 175 mmol) at−72° C. under argon and stirred for 20 min at this temperature. Methyliodide (4.0 mL, 64.3 mmol) is added, the reaction mixture is slowlyheated to RT and stirred for 48 h. The mixture is combined at −72° C.with saturated ammonium chloride solution (38 mL) and divided betweenwater and EtOAc. The aqueous phase is exhaustively extracted with EtOAc,the combined organic phases are washed with water and saturated salinesolution, dried on sodium sulphate, filtered and evaporated down. Thecrude product is crystallised or purified by column chromatography.

Additional alkylation at the nitrogen is obtained using 6 equiv. NaH and7 equiv. methyl iodide. Moreover, an alkylating agent other than methyliodide may be used.

1.3 Preparation of 4-cyano-3-spirocyclopropyloxindole (Method C)

4-cyanooxindole (500 mg, 3.16 mmol) are taken up in 2 mL anhydrous DMFand combined with 248 μL (2.85 mmol) 1,2-dibromoethane. After thesolution has been cooled to 0° C., 379 mg NaH (9.5 mmol, 60% dispersionin oil) are added and the reaction mixture is stirred for 16 h at RT. Itis mixed with several millilitres of saturated aqueous ammonium chloridesolution, extracted 3× with EtOAc and the combined organic phases aredried on sodium sulphate. After elimination of the volatile constituentsin vacuo the residue is purified by chromatography (RP phase).

TABLE 1 t_(ret) method of intermediate [min] [M + H]⁺ analysis

0.44 — C

0.72 187.2 C

0.84 201.2 C

0.75 215.2 C

1.03 243.2 C

1.15 189 L

1.4 Preparation of 4-aminomethyl-3,3-dimethyloxindole (Method D)

4-cyano-3,3-dimethyloxindole (3.70 g, 19.9 mmol) in MeOH (35 mL) and 6 NHCl (15 mL) is mixed with platinum oxide (500 mg) and hydrogenated for17 h at RT under a hydrogen pressure of 5 bar. The reaction mixture isfiltered and evaporated down.

4-cyano-3-spirocyclopropyloxindole is hydrogenated using Raney nickeland methanolic ammonia as solvent (method E).

Further 4-cyanooxindoles may also be hydrogenated analogously.

TABLE 2 t_(ret) method of intermediate [min] [M + H]⁺ analysis

0.13 163.2 C

0.13 191.0 C

0.18 205.2 C

0.16 219.2 C

0.37 247.2 C

1.07 185 G

2. Preparation of the Intermediates/Example Compounds C1 and G1 or (I)2.1 Variant 1

2.1.1 Synthesis of intermediate B-1 (Method F).

2,4,5-trichloropyrimidine A1-1 (0.30 mL, 2.61 mmol) in anhydrous DCM iscombined at 0° C. with N-ethyldiisopropylamine (1.4 mL, 8.0 mmol) and4-aminomethyl-3,3-dimethyloxindole (653 mg, 2.88 mmol) and stirred for30 min at RT. The reaction mixture is washed with dil. ammonium chloridesolution and water, the organic phase is dried on sodium sulphate,filtered, evaporated down and crystallised with water.

The bromine analogue B-2 is prepared analogously starting from5-bromo-2,4-dichloropyrimidine.

TABLE 3 t_(ret) method of intermediate Structure [min] [M + H]⁺ analysisB-1

0.84 337.0 C B-2

2.1.2 General Synthesis of Intermediates/Example Compounds C1 or (I)Starting from Intermediates B (Method G).

A mixture of the corresponding 2-chloropyrimidine B (0.22 mmol), the(hetero)aromatic amine R²—NH₂ (0.29 mmol) and methanesulphonic acid(0.77 mmol) is stirred for 18 h in anhydrous 2-propanol (400 μL) at 90°C. The reaction mixture is purified by preparative

HPLC-MS. The fractions containing the reaction product are freeze-dried.

Instead of methanesulphonic acid p-toluenesulphonic acid ortrifluoroacetic acid may be used. Instead of 2-propanol,4-methyl-2-pentanol may be used as solvent. If the amine used, R²—NH₂,has a BOC protective group this is cleaved in situ under the acidicreaction conditions.

The following intermediates/example compounds C1 or (I) are prepared bythis method (Table 4):

TABLE 4 Intermediate t_(ret) method of (Example) Structure [min] [M +H]⁺ analysis C1-1 (I-1)

0.68 550.2 C C1-2 (I-2)

1.47 509.3 G C1-3¹ (I-3)

2.30 699   K C1-4¹ (I-4)

2.20 743   I C1-5² (I-5)

1.40 535   G C1-6² (I-6)

1.60 491   L C1-7^(2,3) (I-7)

1.91 535.2/537.3 G C1-9^(2,3) (I-238)

1.33 521/523 P C1-10² (I-239)

1.56 535/537 O C1-11² (I-240)

1.59 552/554 O C1-12^(2,3) (I-241)

1.53 551/553 O C1-13² (I-242)

1.75 551/553 O C1-14² (I-243)

1.61 535/537 O C1-15² (I-244)

1.47 549/551 P C1-16^(2,3) (I-245)

1.65 549/551 N C1-17^(2,3) (I-246)

1.62 507/509 O C1-18^(2,3) (I-247)

1.59 491/493 O C1-19² (I-248)

1.75 508/510 O C1-20² (I-249)

1.21 492/494 P C1-21² (I-250)

1.04 491/493 P C1-22² (I-251)

1.43 505/507 P C1-23^(2,3) (I-252)

1.60 477/479 N C1-24^(2,3) (I-253)

1.63 505/507 N C1-25² (I-254)

1.68 508/510 P C1-26² (I-255)

1.68 509/511 N C1-27² (I-256)

1.66 505/507 N C1-28² (I-257)

1.65 506/508 O C1-29² (I-258)

1.75 561/563 N C1-30² (I-259)

1.51 522/524 O C1-31² (I-260)

1.71 543/545 N ¹cf. WO 2002/030927 ²synthesis using a BOC-protectedamine R²—NH₂ and cleaving in situ ³racemic representation of thestructural formula explicitly includes both configurations in each case,i.e.

2.2 Variant 2

2.2.1 Synthesis of Intermediate D-1 (Method H).

2-methylsulphanyl-3H-pyrimidin-4-one (1.50 g, 10.55 mmol) and4-(4-methylpiperazinyl)aniline (1.82 g, 9.50 mmol) in anhydrous NMP (5mL) are stirred for 40 min at 210° C. in a microwave reactor. Thereaction mixture is lyophilised and the residue is purified bychromatography.

TABLE 5 method Inter- t_(ret) [M + of mediate structure [min] H]⁺analysis D-1

0.49 286.2 B2.2.2 Synthesis of intermediate E-1 (method

D-1 (910 mg, 3.19 mmol) in anhydrous acetic acid (5 mL) is combined at0° C. with bromine (180 μL, 3.51 mmol) in anhydrous acetic acid (5 mL)and stirred for 60 min at RT. The precipitated solid is isolated byfiltration.

TABLE 6 method Inter- t_(ret) of mediate structure [min] [M + H]⁺analysis E-1

0.51 364/366 B2.2.3 Synthesis of intermediate F1-1 (method I).

E-1 (780 mg, 2.14 mmol) in phosphorus oxychloride (8 mL) is stirred for30 min at boiling temperature. The mixture is cooled to 0° C., droppedonto ice, neutralised with saturated potassium carbonate solution andexhaustively extracted with DCM. The organic phase is washed with water,dried on sodium sulphate, filtered and evaporated down.

TABLE 7 method Inter- t_(ret) of mediate structure [min] [M + H]⁺analysis F1-1

1.05 382/384 B2.2.4 Synthesis of Example compound I-8 (C1-8) (Method I).

A mixture of F1-1 (70 mg, 0.18 mmol), N-ethyldiisopropylamine (0.64mmol) and 4-aminomethyl-1,3-dihydro-indol-2-one (38 mg, 0.19 mmol) isstirred in anhydrous NMP (400 μL) for 10 min at 120° C. in a microwavereactor (Synthos 3000 made by Anton Paar, Rotor 4×24 MG5). The reactionmixture is purified by preparative HPLC-MS. The fractions containing thereaction product are freeze-dried.

TABLE 8 t_(ret) method of Example Structure [min] [M + H]⁺ analysis I-8(C1-8)

1.54 508.3/510.3 C

2.3 Derivatisation of Intermediates/Example Compounds C1 or (I) to FormOther Intermediates/Example Compounds G1 or (I).

2.3.1 Fmoc cleaving (Method J)

The Fmoc-protected compound C1 (e.g. C₁₋₃ or C₁₋₄) is combined withpiperidine (5 equivalents) in DMF (10 mL/1 g of starting compound) andstirred for 1 h at RT. The mixture is evaporated down and the crudeproduct is purified by column chromatography.

The following components G1 are obtained (Table 9):

TABLE 9 Intermediate t_(ret) method of (Example) Structure educt [min][M + H]⁺ analysis G1-1 (I-9)

C1-3 1.39 477 K G1-2 (I-10)

C1-4 1.43 521 K

2.3.2 Amide Cleaving/Deacetylation (Method K)

C1-1 (1.22 g, 2.22 mmol) is stirred in conc. HCl (0.5 mL) for 15 min at120° C. in a microwave reactor. The reaction mixture is made basic withconcentrated ammonia, diluted with water and exhaustively extracted withDCM. The organic phase is washed with water, dried on magnesiumsulphate, filtered and evaporated down. The crude product is purified bycolumn chromatography.

The following components G1 are obtained (Table 10):

TABLE 10 Intermediate t_(ret) method of (Example) Structure educt [min][M + H]⁺ analysis G1-3 (I-11)

C1-1 1.68 508 G G1-4 (I-12)

C1-2 0.36 467.2 C

3. Preparation of the Intermediates/Example Compounds C2 and G2 or (I)

3.1 General Synthesis of Intermediates F2 (Method L).

The preparation of2-(hetero)arylamino-4-chloro-5-trifluoromethylpyrimidine derivatives F2is carried out analogously to WO 2005/023780. The crude productsobtained are optionally purified by chromatography.

The following components F2 are obtained (Table 11):

TABLE 11 t_(ret) Intermediate Structure [min] [M + H]⁺ method ofanalysis F2-1⁴

1.50 488.1 C F2-2⁵

0.95 549.0 C F2-3⁶

1.24 445.2 C F2-4⁷

1.68 516.2 C F2-5⁸

1.49 500.2 C F2-6⁹

1.09 401.4 B F2-7¹⁰

1.21 571.2 B F2-8¹¹

0.83 444.0 C F2-9¹²

1.58 502.2 C F2-10¹³

1.37 459.2 C F2-11⁸

1.59 502.2 C F2-12¹⁴

2.51 410   I F2-13

F2-14

2.2  459   I F2-15¹⁵

2.61 401   I F2-16

F2-19^(15,16)

2.03 431   O F2-20¹⁵

2.50 469   (M − H) P F2-21¹⁵

2.02 431   (M + H − tBu) O F2-22⁷

1.91 472   O F2-23¹⁵

1.61 469   (M − H) O F2-24^(15,16)

243 469   (M − H) P F2-25¹⁵

2.13 521   (M − H) N F2-26¹⁵

2.13 487   (M − H) N F2-27¹⁵

2.14 483   (M − H) N F2-28¹⁵

1.97 483   (M − H) O F2-29¹⁵

2.15 429   (M + H) − tBu N F2-30¹⁵

1.94 445   (M + H) − tBu O F2-31

F2-32

F2-33

⁴the educt aniline R^(2—)NH₂ is prepared from the nitro compoundanalogously to WO 2006/021548 by reduction using standard methods ⁵theeduct anliline R^(2—)NH₂ is prepared according to US 2008/300242 ⁶theeduct aniline R^(2—)NH₂ is prepared analogously to WO 2002/006232 ⁷theeduct aniline R^(2—)NH₂ is prepared analogously to US 2008/300242 ⁸theeduct aniline R^(2—)NH₂ is prepared from4-fluoro-2-methoxy-1-nitrobenzene analogously to WO 2006/021548 usingstandard methods ⁹the educt aniline R^(2—)NH₂ is prepared according toWO 2006/021548 ¹⁰the educt aniline R^(2—)NH₂ is prepared analogously toWO 2005/016894 ¹¹F2-10 is prepared from the corresponding aminobenzoicacid (cf. WO 2007/115999) by reaction with thionyl chloride and1-methylpiperidin- 4-amine using standard methods ¹²the educt anlineR^(2—)NH₂ is prepared from 2-ethoxy-4-fluoro-1-nitrobenzene analogouslyto WO 2006/021548 using standard methods ¹³the educt anline R^(2—)NH₂ isprepared from 4-fluoro-2-methoxy-1-nitrobenzene and ethylpiperidine-4-carboxylate analogously to WO 2006/021548 using standardmethods ¹⁴the educt aniline R^(2—)NH₂ is prepared from the correspondingnitro compound by reduction ¹⁵the educt anline R^(2—)NH₂ is preparedaccording to or analogously to the following method:

4-chloro-2-methoxy-nitrobenzene (2.0 g, 9.6 mmol) is taken up in 40 mLanhydrous dioxane in an argon atmosphere. 3-pyridineboric acid (1.77 g,14.4 mmol) is added to this mixture, followed by degassed sodiumcarbonate solution (10 mL, 3 M) and bis-triphenylphosphine-palladium(II) chloride (337 mg, 48 mmol). The reaction mixture is stirred for 16h at 80° C. under an argon atmosphere. After further addition of sodiumcarbonate (3.2 g) and 0.1 eq palladium catalyst the mixture is stirredagain for 4 h at 85° C.

After cooling, the reaction mixture is poured onto water (100 mL),extracted 3× with ethyl acetate (20 mL aliquots), the combined organicphases are dried on magnesium sulphate and evaporated down in vacuo.Chromatographic purification through silica gel with cyclohexane/ethylacetate yields the coupling product.

The coupling product obtained (2.04 g, 8.63 mmol) is taken up in glacialacetic acid (100 mL), mixed with platinum oxide (100 mg, 0.1 eq) andhydrogenated for 48 h at RT and 9 bar of H₂ pressure. The reactionmixture is filtered through Celite, the volatile constituents areeliminated in vacuo and the solution obtained is poured into saturated,aqueous sodium hydrogen carbonate solution (50 mL). It is extracted 3×with ethyl acetate (30 mL aliquots), the combined organic phases aredried on magnesium sulphate, then after evaporation purified bychromatography (silica gel, cyclohexane/ethyl acetate) and the anilineis obtained.

The aniline obtained (971 mg, 4.71 mmol) is taken up in dichloromethane(50 mL), di-tert-butylcarbonate (1.03 g, 4.71 mmol) is added and thereaction mixture is stirred for 3 h at RT. After concentration in vacuothe crude product of the Boc-protected aniline is obtained, which isfurther used directly.

¹⁶racemic representation of the structural formula always explicitlyincludes both configurations, i.e.

3.2 Derivatisation of Intermediates F2 to Form Further Intermediates F2.3.2.1 Synthesis of Intermediate F2-17 (Boc Cleaving, Method M)

F2-17 (200 mg, 0.43 mmol) in anhydrous DCM (5 mL) is combined at 0° C.with TFA (30 equivalents) and stirred for 2 h at RT. The mixture ismixed with water, neutralised with 2 N NaOH and exhaustively extractedwith DCM. The organic phase is washed with water, dried on magnesiumsulphate, filtered and evaporated down.

3.2.2 Synthesis of intermediate F2-18 (reductive amination, method N)

F2-17 (156 mg, 0.43 mmol) in anhydrous DCM (10 mL) is combined with 37%aqueous formaldehyde solution (1.2 equivalents) and acetic acid (2.4equivalents) and stirred for 30 min at RT. Sodium triacetoxyborohydride(1.4 equivalents) is added. The reaction mixture is stirred for 16 h andthen evaporated down. The residue is taken up in EtOAc, washed withsaturated sodium hydrogen carbonate solution and saturated salinesolution, dried on magnesium sulphate, filtered and evaporated down. Thecrude product is optionally purified by column chromatography.

TABLE 12 method Inter- t_(ret) of mediate Structure [min] [M + H]⁺analysis F2-17

1.5  359 I F2-18

1.53 373 I3.3 General Synthesis of Intermediates/Example Compounds C2 or (I)Starting from Intermediates F2 (Method F).

The reaction of 4-chloropyrimidine components F2 with correspondingamines R⁴—NH₂ is carried out according to method F (cf. 2.1.1)

TABLE 13 Intermediate t_(ret) method of (Example) Structure [min] [M +H]⁺ analysis C2-1 (I-13)

1.11 614.4 C C2-2 (I-14)

0.82 571.2 C C2-3 (I-15)

1.35 642.4 C C2-4 (I-16)

1.17 654.4 C C2-5 (I-17)

1.35 656.4 C C2-6 (I-18)

1.22 642.3 C C2-7 (I-19)

1.31 656.4 C C2-8 (I-20)

1.14 628.4 C C2-9 (I-21)

1.10 613.4 C C2-10 (I-22)

2.13 546   I C2-11 (I-23)

2.41 592   K C2-12 (I-24)

2.24 611   I C2-13

1.30 536.2/ 538.2 C C2-14 (I-25)

1.87 703.3 G C2-15 (I-26)

1.76 675.3 G C2-16¹⁷ (I-261)

1.92 641   O C2-17 (I-262)

1.61 625   P C2-18 (I-263)

1.81 626   O C2-19 (I-264)

1.99 625   N C2-20¹⁷ (I-265)

2.24 625   P C2-21 (I-266)

2.03 677   N C2-22 (I-267)

2.03 643   N C2-23 (I-268)

2.02 639   N C2-24 (I-269)

1.87 639   O C2-25 (I-270)

2.03 639   N C2-26 (I-271)

1.83 655   O C2-27 (I-272)

C2-28 (I-273)

C2-29 (I-274)

C2-30 (I-275)

¹⁷racemic representation of the structural formula always explicitlyincludes both configurations, i.e.

3.4 Derivatisation of Intermediates/Example Compounds C2 or (I) to FormOther Intermediates/Example Compounds G2 or (I).

3.4.1 Boc cleaving (Method O)

C2-1 (2.0 g, 3.26 mmol) in anhydrous DCM (20 mL) is combined at 0° C.with TFA (5 mL) and stirred for 3 h at RT. The mixture is mixed withwater, neutralised with 2 N NaOH and exhaustively extracted with DCM.The organic phase is washed with water, dried on magnesium sulphate,filtered and evaporated down. The crude product is optionally purifiedby column chromatography.

The following components G2 (Table 14) are prepared by this method(alternatively, the cleaving may be carried out hydrogenolytically ifthe Z protective group is used, method P):

TABLE 14 Intermediate t_(ret) method of (Example) Structure [min] [M +H]⁺ analysis G2-1 (I-27)

0.54 514.2 C G2-2 (I-28)

0.63 542.0 C G2-3 (I-29)

0.58 554.2 C G2-4 (I-30)

1.88 556   G G2-5 (I-31)

0.67 542.1 C G2-6 (I-32)

1.74 528.3 G G2-7 (I-33)

1.90 556.3 G G2-8 (I-34)

0.70 556.4 C G2-9 (I-35)

1.52 511   I G2-156¹⁸ (I-276)

1.67 541   O G2-157 (I-277)

1.58 525   P G2-158 (I-278)

1.59 526   O G2-159 (I-279)

1.17 525   P G2-160¹⁸ (I-280)

1.71 525   O G2-161 (I-281)

1.77 577   N G2-162 (I-282)

1.72 543   N G2-163 (I-283)

1.72 539   N G2-164 (I-284)

1.69 539   O G2-165 (I-285)

1.82 539   N G2-166 (I-286)

1.66 555   O G2-167 (I-287)

G2-168 (I-288)

G2-169 (I-289)

G2-170 (I-290)

¹⁸racemic representation of the structural formula always explicitlyincludes both configurations, i.e.

3.4.2 Ketal Cleaving (Method Q)

C2-2 (1.20 g, 2.10 mmol) in 6 N HCl (10 mL) and MeOH (5 mL) is stirredfor 18 h at RT. After the addition of 1.5 mL concentrated HCl themixture is stirred for a further 2 h at RT. The reaction mixture is madebasic with concentrated ammonia, diluted with water and exhaustivelyextracted with DCM. The organic phase is washed with water, dried onmagnesium sulphate, filtered and evaporated down. The crude product isoptionally purified by column chromatography.

The following components G2 (Table 15) are prepared by this method:

TABLE 15 Intermediate t_(ret) method of (Example) Structure [min] [M +H]⁺ analysis G2-10 (I-36)

0.93 527.0 B G2-11 (I-37)

0.90 555.2 C

3.4.3 Alkylester Cleavage (Method R)

C2-9 (320 mg, 0.52 mmol) in THF (2 mL) and EtOH (0.5 mL) is combinedwith 1N NaOH (3 equiv.) and stirred for 16 h at RT. The reaction mixtureis neutralised with 1N HCl, evaporated down to one third of the volumeand divided between water and DCM. The aqueous phase is exhaustivelyextracted with DCM. The combined organic phase is washed with water,dried on magnesium sulphate, filtered and evaporated down. The crudeproduct is optionally purified by column chromatography.

TABLE 16 Intermediate t_(ret) method of (Example) Structure [min] [M +H]⁺ analysis G2-12 (I-38)

0.83 585.4 C

3.4.4 Debenzylation (Method S)

C2-10 (155 mg, 0.27 mmol) is hydrogenated in the presence of Pd(OH)₂ inEtOH (6.5 mL) 16 h at RT under a hydrogen pressure of 1 bar. Thereaction mixture is filtered and the filtrate is evaporated down.

TABLE 17 t_(ret) method of Intermediate Structure [min] [M + H]⁺analysis G2-13

1.6 474 I

3.4.5 Benzylester Cleavage (Method T)

Benzylester cleavage on C2-11: The benzylester cleavage is carried outanalogously to the debenzylation (method S, 3.4.4).

TABLE 18 t_(ret) method of Intermediate Structure [min] [M + H]⁺analysis G2-14

1.89 502 K

3.4.6 by SUZUKI Coupling

3.4.6.1 SUZUKI Reaction (Method U)

N-Boc-1,2,5,6-tetrahydropyridine-4-boric acid pinacol ester (192 mg,0.60 mmol), C2-13 (268 mg, 0.50 mmol),bis(triphenylphosphine)palladium(II)chloride (36 mg, 0.03 mmol) andsodium carbonate (159 mg, 1.5 mmol) are stirred in water (1.5 mL) anddioxane (3 mL) under argon for 20 min at 120° C. in a microwave reactor.The reaction mixture is combined with EtOH (80 mL), filtered and useddirectly in the next step.

TABLE 19 Intermediate t_(ret) method of (Example) Structure [min] [M +H]⁺ analysis G2-15 (I-39)

1.47 639.4 C

3.4.6.2 Reduction/Hydrogenation (Method V)

The reaction mixture from the previous step is hydrogenated in theH-Cube throughflow reactor (Thalos Nano, 40° C., flow: 1 mL/min, Full H₂Mode, catalyst: 10% Pd/C). The reaction mixture is evaporated down.

TABLE 20 Intermediate t_(ret) method of (Example) Structure [min] [M +H]⁺ analysis G2-16 (I-40)

1.43 641.4 C3.4.6.3 Boc Cleaving (Cf. Method 0, 3.4.1)

The cleaving der Boc-protective group is carried out analogously tomethod O.

TABLE 21 intermediate t_(ret) method of (Example) Structure [min] [M +H]⁺ analysis G2-17 (I-41)

2.25 541.3 G

4. Preparation of Further Example Compounds (I) by Derivatisation ofExample Compounds/Intermediates C1 or C2, G1 or G2 and (I) 4.1 Acylation

4.1.1 General synthesis: acylation with acid chlorides (Method W)

The corresponding compound C1, C2, G1 or G2 is taken up in anhydrousDCM, combined with the acid chloride (1.4 equivalents) and triethylamine(3 equivalents) and stirred for 3 h at RT. The reaction mixture isevaporated down, the residue is taken up in DMSO and purified bypreparative HPLC-MS. The fractions containing the reaction product arefreeze-dried.

4.1.2 General Synthesis: Amide Coupling with Acids (Method X)

The starting compound (50 mg) in anhydrous DMSO (1 mL) is combined withTBTU (1.5 equivalents), triethylamine (1.5 equivalents) and thecorresponding carboxylic acid (5 equivalents) and stirred for 5 h at RT.The reaction mixture is purified by preparative HPLC-MS. The fractionscontaining the reaction product are freeze-dried.

(Acid components which in turn contain a Boc-protected aminofunctionality are deprotected in a subsequent step by reacting with TFAor HCl.)

The following Example compounds (Table 22) are obtained by acylation ofcorresponding precursors. The Example compounds obtained first may beoptionally be deprotected by conventional methods and/or reacted byfurther standard reactions (e.g. direct alkylation, reductivealkylation, carboxylic acid amide formation, sulphonamide formation,acylation etc.) to form other Example compounds.

TABLE 22 t_(ret) method of # Structure educt [min] [M + H]⁺ analysisI-42 (G1-5)

G1-2 2.75 608 H I-43 (G1-6)

G1-1 2.7 562 H I-44 (G1-7)

G1-1 3.59 674 H I-45 (G1-8)

G1-1 3.47 635 H I-46 (G1-9)

G1-1 3.56 648 H I-47 (G1-10)

G1-1 3.62 661 H I-48 (G1-11)

G1-1 3.13 585 H I-49 (G1-12)

G1-1 2.72 574 H I-50 (G1-13)

G1-1 2.62 534 H I-51 (G1-14)

G1-1 2.62 548 H I-52 (G1-15)

G1-1 2.61 560 H I-53 (G1-16)

G1-2 3.1 648 H I-54 (G1-17)

G1-2 3.26 609 H I-55 (G1-18)

G1-2 2.75 620 H I-56 (G1-19)

G1-2 2.7 606 H I-57 (G1-20)

C1-6 1.87 620.2/ 622.2 G I-58 (G1-21)

1.86 592.3 G I-59 (G1-22)

G1-3 1.91 633.3 G I-60 (G1-23)

G1-3 1.81 633.3 G I-61 (G1-24)

G1-3 1.74 648.2 G I-62 (G1-25)

G1-3 1.80 593.3 G I-63 (G1-26)

G1-3 1.84 633.3 G I-64 (G1-27)

G1-3 1.87 621.3 G I-65 (G1-28)

G1-3 1.72 633.3 G I-66 (G1-29)

G1-4 1.16 552.2 G I-67 (G1-30)

C1-5 1.40 562.3 G I-68 (G1-31)

1.90 636.2/ 638.3 G I-69 (G1-32)

C1-5 1.37 576.2 G I-70 (G2-18)

G2-1 1.64 556.3 G I-71 (G2-19)

G2-1 1.74 585.3 G I-72 (G2-20)

G2-1 1.89 586.3 G I-73 (G2-21)

G2-8 2.02 614.3 G I-74 (G2-22)

G2-9 3.16 624 H I-75 (G2-23)

G2-9 3.05 596 H I-76 (G2-24)

G2-5 1.88 613.3 G I-77 (G2-25)

G2-5 1.78 584.3 G I-78 (G2-26)

G2-6 1.75 570.3 G I-79 (G2-27)

G2-7 1.88 598.3 G I-80 (G2-28)

G2-3 1.76 596 G I-81 (G2-29)

G2-3 1.86 625.3 G I-82 (G2-30)

G2-3 1.91 612.3 G I-83 (G2-31)

G2-5 1.80 614.3 G I-84 (G2-32)

G2-5 1.96 627.3 G I-85 (G2-33)

G2-5 1.84 628 G I-86 (G2-34)

G2-5 1.93 655.3 G I-87 (G2-35)

G2-5 1.93 667.2 G I-88 (G2-36)

G2-5 1.84 682.3 G I-89 (G2-37)

G2-5 1.88 641.3 G I-90 (G2-38)

G2-5 1.91 667.2 G I-91 (G2-39)

G2-1 1.73 599.2 G I-92 (G2-40)

G2-1 1.82 627.2 G I-291¹⁹ (G1-63)

C1-7 1.34 632/634 P I-292 (G1-64)

C1-5 1.32 563/565 P I-293 (G1-65)

C1-5 1.33 562/564 P I-294 (G1-66)

C1-5 1.24 534/536 P I-295 (G1-67)

C1-5 1.32 588/590 P I-296 (G1-68)

C1-19 1.31 565/567 P I-297 (G1-69)

C1-5 1.35 577/579 P I-298 (G1-70)

C1-5 1.27 549/551 P I-299 (G1-71)

G1-1 1.29 574/576 P I-300 (G1-72)

C1-19 1.38 593/595 P ¹⁹racemic representation of the structural formulaalways explicitly includes both configurations, i.e.

4.2 Reductive Amination 4.2.1 General Synthesis: Reductive Amination onAmines C1, C2, G1 or G2 (Method Y)

The corresponding compound C1, C2, G1 or G2 is taken up in anhydrousNMP, combined with the carbonyl compound (3 equivalents) and sodiumtriacetoxyborohydride (2.9 equivalents) and stirred for 1.5 h at RT. Thereaction mixture is combined with formic acid and purified bypreparative HPLC-MS. The fractions containing the reaction product arefreeze-dried.

The following Example compounds (Table 23) are obtained by reductiveamination of the corresponding precursors. The Example compoundsobtained first may optionally be deprotected by conventional methodsand/or reacted by further standard reactions (e.g. direct alkylation,reductive alkylation, carboxylic acid amide formation, sulphonamideformation, acylation etc.) to form further Example compounds.

TABLE 23 t_(ret) method of # Structure educt [min] [M + H]⁺ analysisI-93 (G1-33)

G1-1 2.59 533 K I-94 (G1-34)

1.65 492.0 G I-95 (G1-35)

G1-3 1.80 592.3 G I-96 (G1-36)

G1-3 2.01 562.3 G I-97 (G1-37)

G1-3 1.77 522.2 G I-98 (G1-38)

G1-3 1.95 550 G I-99 (G1-39)

G1-3 1.85 536 G I-100 (G1-40)

G1-3 1.94 521.3 G I-101 (G1-41)

G1-3 1.98 562.3 G I-102 (G1-42)

G1-4 1.17 481.2 G I-103 (G1-43)

C1-6 1.94 549.3/ 551.2 G I-104 (G2-41)

G2-5 1.86 556.3 G I-105 (G2-42)

G2-8 2.09 640.3 G I-106 (G2-43)

G2-8 2.14 598.3 G I-107 (G2-44)

G2-8 2.01 584.3 G I-108 (G2-45)

G2-8 1.92 570.3 G I-109 (G2-46)

G2-8 2.15 610.3 G I-110 (G2-47)

G2-1 1.66 639.3 G I-111 (G2-48)

G2-1 1.95 639.3 G I-112 (G2-49)

G2-1 1.91 637.3 G I-113 (G2-50)

G2-1 1.74 636.3 G I-114 (G2-51)

G2-1 1.86 625.3 G I-115 (G2-52)

G2-1 1.80 681.3 G I-116 (G2-53)

G2-1 1.89 556.3 G I-117 (G2-54)

G2-1 1.91 611.3 G I-118 (G2-55)

G2-1 1.77 598.3 G I-119 (G2-56)

G2-1 1.71 528.3 G I-120 (G2-57)

G2-1 1.80 605.3 G I-121 (G2-58)

G2-1 1.69 641.3 G I-122 (G2-59)

G2-1 1.82 655.3 G I-123 (G2-60)

G2-1 1.57 668.3 G I-124 (G2-61)

G2-1 1.66 704.3 G I-125 (G2-62)

G2-1 1.55 675.3 G I-126 (G2-63)

G2-4 2.00 640.3 G I-127 (G2-64)

G2-4 1.97 570 G I-128 (G2-65)

G2-4 2.16 598.3 G I-129 (G2-66)

G2-4 2.06 584.3 G I-130 (G2-67)

G2-4 2.07 653.3 G I-131 (G2-68)

G2-8 1.97 610.5 G I-132 (G2-69)

G2-8 1.82 653.3 G I-133 (G2-70)

1.43 527 I I-134 (G2-71)

G2-9 3.09 553 H I-135 (G2-72)

G2-5 2.00 639.3 G I-136 (G2-73)

G2-5 2.03 584.3 G I-137 (G2-74)

G2-2 2.17 584.3 G I-138 (G2-75)

G2-6 1.82 542.3 G I-139 (G2-76)

G2-6 2.00 570.3 G I-140 (G2-77)

G2-6 1.91 556.3 G I-141 (G2-78)

G2-6 1.76 584.3 G I-142 (G2-79)

G2-7 1.96 570.3 G I-143 (G2-80)

G2-7 2.13 598.3 G I-144 (G2-81)

G2-7 2.04 584.3 G I-145 (G2-82)

G2-7 2.06 653.3 G I-146 (G2-83)

G2-7 1.90 612.3 G I-147 (G2-84)

G2-3 1.95 651.3 G I-148 (G2-85)

G2-3 2.05 608.3 G I-149 (G2-86)

G2-3 2.04 608.3 G I-150 (G2-87)

G2-3 1.86 638.3 G I-151 (G2-88)

G2-3 1.86 568.3 G I-152 (G2-89)

G2-3 1.99 596.3 G I-153 (G2-90)

G2-3 1.94 582.3 G I-154 (G2-91)

G2-3 1.80 610 G I-155 (G2-92)

G2-5 2.09 596.3 G I-156 (G2-93)

G2-5 1.81 598 G I-157 (G2-94)

G2-5 1.95 570.3 G I-158 (G2-95)

G2-5 1.82 667.3 G I-159 (G2-96)

G2-17 2.29 583.3 G I-160 (G2-97)

1.78 554.2 G I-161 (G2-98)

1.79 489.3 G I-162 (G2-99)

G2-5 2.08 596.3 G I-163 (G2-100)

G2-5 2.06 697.2 G I-164 (G2-101)

G2-5 2.07 622.2 G I-165 (G2-102)

G2-1 1.94 568.2 G I-166 (G2-103)

G2-1 1.92 669.2 G I-301²⁰ (G2-171)

G2-156 1.58 613 P I-302 (G2-172)

G2-17 1.38 613 M I-303 (G2-173)

G2-157 1.53 597 M I-304 (G2-174)

G2-5 1.45 614 P I-305 (G2-175)

G2-158 1.42 598 P I-306²⁰ (G2-176)

G2-160 1.52 597 M I-307 (G2-177)

G2-158 1.36 540 P I-308 (G2-178)

G2-159 1.46 539 P I-309 (G2-179)

G2-159 1.36 597 M I-310 (G2-180)

G2-161 1.41 649 M I-311 (G2-181)

G2-162 1.40 615 M I-312 (G2-182)

G2-163 1.39 611 M I-313 (G2-183)

G2-164 1.33 611 M I-314 (G2-184)

G2-165 1.42 611 M I-315 (G2-185)

G2-166 1.33 627 P I-316²⁰ (G1-73)

C1-7 1.51 647/649 P I-317 (G1-74)

C1-10 1.38 608/610 P I-318²⁰ (G1-75)

C1-7 2.07 607/609 M I-319 (G1-76

C1-7 1.51 (4.16) 607/609 M (Q) I-320 (G1-77)

C1-7 1.51 (5.02) 607/609 M (Q) I-321 (G1-78)

C1-11 1.41 624/626 P I-322²⁰ (G1-79)

C1-12 1.54 623/625 P I-323 (G1-80)

C1-13 2.14 623/625 M I-324 (G1-81)

C1-14 1.91 607/609 M I-325²⁰ (G1-82)

C1-9 1.47 633/635 P I-326 (G1-83)

C1-5 1.50 603/605 P I-327²⁰ (G1-84)

C1-17 1.38 579/581 M I-328²⁰ (G1-85)

C1-18 1.49 563/565 P I-329²⁰ (G1-86)

C1-18 1.58 603/605 P I-330 (G1-87)

C1-20 1.27 506/508 P I-331 (G1-88)

C1-19 1.54 579/581 M I-332 (G1-89)

C1-5 1.42 505/507 A I-333²⁰ (G1-90)

C1-23 1.44 589/591 P I-334 (G1-91)

C1-21 1.31 563/565 M I-335 (G1-92)

G1-3 1.4  580/582 P I-336 (G1-93)

C1-20 1.37 564/566 P I-337 (G1-94)

C1-26 1.36 581/583 M I-338 (G1-95)

C1-27 1.35 577/579 M I-339 (G1-96)

C1-28 1.33 577/579 M I-340 (G1-97)

C1-29 1.46 633/635 M I-341 (G1-98)

C1-30 1.27 593/595 M I-342 (G1-99)

C1-31 1.37 615/617 M I-343 (G2-186)

G2-167 I-344²⁰ (G2-187)

G2-168 I-345²⁰ (G2-188)

G2-169 I-346²⁰ (G2-189)

G2-170 I-347²⁰ (G1-100)

I-348²⁰ (G1-101)

I-349²⁰ (G1-102)

²⁰racemic representation of the structural formula always explicitlyincludes both configurations, i.e.

4.2.2 General Synthesis: Reductive Amination on Carbonyl Compounds G1 orG2 (cf. Method Y)

Reductive amination using G1 or G2 with a carbonyl substructure andamines is carried out according to method Y.

The following Example compounds (Table 24) are obtained by reductiveamination of corresponding precursors. The Example compounds obtainedfirst may optionally be deprotected by conventional methods and/or bereacted by further standard reactions (e.g. direct alkylation, reductivealkylation, carboxylic acid amide formation, sulphonamide formation,acylation etc.) to obtain further Example compounds.

TABLE 24 method t_(ret) of # Structure educt [min] [M + H]⁺ analysisI-167 (G2-104)

G2-11 1.9  614.3 G I-168 (G2-105)

G2-11 2.04 642.3 G I-169 (G2-106)

G2-11 1.84 614   G I-170 (G2-107)

G2-11 2.02 654.3 G I-171 (G2-108)

G2-11 1.90 626.3 G I-172 (G2-109)

G2-11 1.83 626.3 G I-173 (G2-110)

G2-11 2.07 642.3 G I-174 (G2-111

G2-11 1.84 626.3 G I-175 (G2-112)

G2-11 1.98 628.3 G I-176 (G2-113)

G2-11 2.04 596   G I-177 (G2-114)

G2-11 1.84 640.3 G I-178 (G2-115)

G2-10 1.92 613.3 G I-179 (G2-116)

G2-10 1.78 586.3 G I-180 (G2-117)

G2-11 2.14 610.3 G I-181 (G2-118)

G2-11 2.00 584.3 G I-182 (G2-119)

G2-10 2.00 639.3 G I-183 (G2-120)

G2-10 2.09 613.3 G I-184 (G2-121)

G2-10 1.88 556.3 G I-185 (G2-122)

G2-10 2.09 627.3 G I-186 (G2-123)

G2-10 1.72 586.3 G I-187 (G2-124)

G2-10 1.89 542.3 G I-188 (G2-125)

G2-10 1.72 612.3 G I-189 (G2-126)

G2-10 2.03 582.3 G I-190 (G2-127)

G2-10 1.92 637.5 G I-191 (G2-128)

G2-10 1.66 572.3 G I-192 (G2-129)

G2-10 1.89 626.3 G I-193 (G2-130)

G2-10 1.83 694.3 G I-194 (G2-131)

G2-10 1.86 599.3 G I-195 (G2-132)

G2-10 1.84 621.3 G I-196 (G2-133)

G2-10 1.76 598.3 G I-197 (G2-134)

G2-10 1.85 600.3 G I-198 (G2-135)

G2-10 1.88 639.3 G I-199 (G2-136)

G2-10 2.00 632.3 G I-200 (G2-137)

G2-10 1.74 681.3 G I-201 (G2-138)

G2-10 1.69 639.3 G I-202 (G2-139)

G2-10 1.73 611.3 G

4.3 Sulphonylation 4.3.1 General Synthesis: Sulphonylation (Method Z)

The corresponding compound C1, C2, G1 or G2 is taken up in anhydrousDCM, combined with the sulphonic acid chloride (1.4 equivalents) andtriethylamine (3 equivalents) and stirred for 3 h at RT. The reactionmixture is evaporated down, the residue is taken up in DMSO and purifiedby preparative HPLC-MS. The fractions containing the reaction productare freeze-dried.

The following Example compounds (Table 25) are obtained bysulphonylation of corresponding precursors. The Example compoundsobtained first may optionally be deprotected by conventional methodsand/or reacted by further standard reactions (e.g. direct alkylation,reductive alkylation, carboxylic acid amide formation, sulphonamideformation, acylation etc.) to form further Example compounds.

TABLE 25 method t_(ret) of # Structure educt [min] [M + H] analysisI-203 (G1-44)

C1-5 1.38 569.3 G4.4 Direct alkylation

4.4.1 General Synthesis: Alkylation (Method AA)

The corresponding compound C1, C2, G1 or G2 is taken up in anhydrousDMSO, combined with the alkylhalide (1.2 equivalents) and triethylamine(3 equivalents) and stirred for 12 h at RT. The reaction mixture ispurified by preparative HPLC-MS. The fractions containing the reactionproduct are freeze-dried.

The following Example compounds (Table 26) are obtained by directalkylation of corresponding precursors. The Example compounds obtainedfirst may optionally be deprotected by conventional methods and/orreacted by further standard reactions (e.g. direct alkylation, reductivealkylation, carboxylic acid amide formation, sulphonamide formation,acylation etc.) to form further Example compounds.

TABLE 26 method t_(ret) of # Structure educt [min] [M + H]⁺ analysisI-204 (G1-45)

G1-1  4.91 535 J I-205 (G1-46)

G1-1  2.57 522 H I-206 (G1-47)

G1-1  2.58 548 I I-207 (G1-48)

G1-1  2.65 583 I I-208 (G1-49)

G1-2  2.73 579 H I-209 (G1-50)

G1-2  2.63 565 H I-210 (G1-51)

G1-2  2.73 593 J I-211 (G1-52)

G1-1  2.63 549 H I-212 (G1-53)

G1-2  2.71 581 H I-213 (G1-54)

G1-1  2.65 537 H I-214 (G1-55)

C1-6  1.82 579.2/581.3 G I-215 (G1-56)

G1-4  1.19 525.3 G I-216 (G1-57)

C1-5  1.35 597.3 G I-217 (G1-58)

C1-5  1.35 535.2 G I-218 (G1-59)

C1-5  1.36 549.3 G I-219 (G1-60)

C1-5  1.36 562.3 G I-220 (G1-61)

C1-5  1.31 548.3 G I-221 (G1-62)

C1-6  2.00 593.2/595.2 G I-222 (G2-140)

G2-1  1.77 560.3 G I-223 (G2-141)

G2-1  1.61 558.3 G I-224 (G2-142)

G2-1 1.75 572.3 G  I-350²¹ (G2-190)

 G2-156 1.49 599 P  I-351²¹ (G2-191)

 G2-156 1.39 585 P I-352 (G2-192)

 G2-159 1.46 583 P I-353 (G2-193)

G2-5  1.39 600 P  I-354²¹ (G2-194)

 G2-160 1.40 569 P I-355 (G2-195)

 G2-159 1.38 569 P  I-356²¹ (G2-196)

 G2-160 1.48 583 P  I-357²¹ (G1-103)

C1-9  1.39 579/581 P  I-358²¹ (G1-104)

C1-9  1.29 565/567 P  I-359²¹ (G1-105)

C1-7  1.47 593/595 P  I-360²¹ (G1-106)

C1-12 1.47 609/611 P  I-361²¹ (G1-107)

C1-12 1.37 595/597 P I-362 (G1-108)

C1-7  1.63 (7.54) 593/595 P (R) I-363 (G1-109)

C1-7  1.63 (8.69) 593/595 P (R)  I-364²¹ (G1-110)

C1-7  1.62 579/581 P  I-365²¹ (G1-111)

C1-9  1.32 592/594 P  I-366²¹ (G1-112)

C1-7  1.36 606/608 P I-367 (G1-113)

C1-15 1.5  607/609 P  I-368²¹ (G1-114)

C1-16 1.49 607/609 P I-369 (G1-115)

C1-11 1.37 610/612 P I-370 (G1-116)

C1-5  1.36 562/564 P  I-371²¹ (G1-117)

C1-17 1.45 565/567 P  I-372²¹ (G1-118)

C1-17 1.34 551/553 P  I-373²¹ (G1-119)

C1-18 1.41 549/551 P I-374 (G1-120)

C1-19 1.41 546/548 P I-375 (G1-121)

C1-5  1.38 530/532 P I-376 (G1-122)

C1-21 1.98 549/551 M I-377 (G1-123)

C1-5  1.32 563/565 M I-378 (G1-124)

C1-22 1.38 577/579 M  I-379²¹ (G1-125)

C1-23 1.30 548/550 P  I-380²¹ (G1-126)

C1-23 1.44 535/537 P  I-381²¹ (G1-127)

C1-23 1.25 521/523 P  I-382²¹ (G1-128)

C1-18 1.32 535/537 P  I-383²¹ (G1-129)

C1-18 1.32 562/564 P  I-384²¹ (G1-130)

C1-24 1.46 563/565 P I-385 (G1-131)

C1-22 1.47 563/565 P I-386 (G1-132)

C1-25 1.34 566/568 P ²¹racemic representation of the structural formulaalways explicitly includes both configurations, i.e.,

4.5 Amide Coupling to Carboxylic Acid Components G1 or G2 (Cf. Method X)

The amide coupling is carried out analogously to method X (i.e. withTBTU), except that in this case the corresponding compound G1 or G2 hasthe carboxyl function and is reacted with an amine.

The following Example compounds (Table 27) are obtained by amidecoupling of corresponding precursors. The Example compounds obtainedfirst may optionally be deprotected by conventional methods and/orreacted by further standard reactions (e.g. direct alkylation, reductivealkylation, carboxylic acid amide formation, sulphonamide formation,acylation etc.) to form further Example compounds.

TABLE 27 method t_(ret) of # Structure educt [min] [M + H]⁺ analysisI-225 (G2-143

G2-14 1.97 612.3 G I-226 (G2-144)

G2-12 1.75 681.5 G I-227 (G2-145)

G2-12 1.58 598.5 G I-228 (G2-146)

G2-14 1.77 598.3 G I-229 (G2-147)

1.82 584.2 G I-230 (G2-148)

G2-12 1.70 612.5 G I-231 (G2-149)

1.90 612.3 G I-232 (G2-150)

1.80 570.3 G I-233 (G2-151)

1.91 626.2 G I-234 (G2-152)

G2-14 3.86 571 H I-235 (G2-153)

1.19 525.3 G

4.6 Derivatisation on Phenolic Components G1 or G2 (Method AB)

The corresponding compound G1 or G2, an organic halide (e.g.alkylhalide, 0.9 equivalents) and potassium carbonate (1.9 equivalents)are stirred in DMF for 48 h at 100° C. The reaction mixture is dividedbetween DCM and saturated saline solution and the aqueous phase isexhaustively extracted. The organic phase is dried on sodium sulphate,filtered and evaporated down. The crude product is purified bypreparative HPLC. The fractions containing the reaction product arefreeze-dried.

Alternatively derivatisation may also be carried out on the phenolichydroxyl function by MITSONOBU reaction.

The following Example compounds (Table 28) are obtained by alkylation ofcorresponding precursors. The Example compounds obtained first mayoptionally be deprotected by conventional methods and/or reacted byfurther standard reactions (e.g. direct alkylation, reductivealkylation, carboxylic acid amide formation, sulphonamide formation,acylation etc.) to form further Example compounds.

TABLE 28 method t_(ret) of # Structure educt [min] [M + H]⁺ analysisI-236 (G2-154)

G2-13 1.97 612.3 G  I-237²² (G2-155)

G2-10 1.63 529.3 G ²²synthesis by reduction of G2-10

The following Examples describe the biological activity of the compoundsaccording to the invention, without restricting the invention to theseExamples.

Compounds of general formula (I) are characterised by their manypossible applications in the therapeutic field. Particular mentionshould be made of those applications in which the inhibiting effect onthe proliferation of cultivated human tumour cells but also on theproliferation of other cells such as endothelial cells, for example, areinvolved.

Insulin-Like Growth Factor-1 Receptor (IGF-1R)-Kinase Assay

The kinase activity is measured by DELFIA® assay (dissociation-enhancedlanthanide fluorescence immunoassay, Perkin Elmer). The cytoplasmickinase domain of human IGF-1R (amino acids 964-1370) is expressed as afusion protein with a glutathione-S-transferase tag (IGF-1R-GST) in HighFive™ Cells (Invitrogen). Enzyme activity is measured in the presence ofsubstances and a control substance. Poly-glutamate-tyrosine peptide(pEY, Sigma Aldrich) and biotinylated pEY (bio-pEY) are used as reactionsubstrates.

10 μL of substance in 25% DMSO are mixed with 30 μL of of IGF-1R-GSTsolution (67 mM HEPES pH 7.4, 15 μg/mL pEY, 1.7 μg/mL bio-pEY, 13.3 mMMgCl₂, 3.3 mM dithiothreitol, 0.0033% Brij 35, 2 ng IGF-1R-GST) in96-well plates. The reactions are started with 10 μL of a 750 μM ATPsolution. After 40 min at RT the reactions are stopped with 50 μL ofstop solution (250 mM EDTA, 20 mM HEPES pH 7.4). 90 μL from eachreaction are transferred onto streptavidin-coated 96-well plates. After120 min incubation at RT the plates are washed three times with 200 μLphosphate-buffered saline (PBS) per well. The plates are incubated for60 min with 100 μL of europium-coupled antibody against phospho-tyrosine(diluted 1/2000 in Perkin Elmer DELFIA assay buffer) per well. Theplates are washed three times with 200 μL per well of DELFIA washingbuffer. 100 μL DELFIA Enhancement Solution (Perkin Elmer) is added toeach well, and the plates are incubated for 10 min. The fluorescencesignal is measured with a Wallac Victor TRF Reader. IC₅₀ values for theinhibition of the IGF-1R-kinase activity are calculated using theprogrammes Fifty (Version 2) and GraphPad (Version 3.0).

Table 29 shows the IC₅₀ values of the example compounds determined usingthe above assay.

TABLE 29 IGFIR # IC₅₀[nM] I-2 21 I-7 0.69 I-8 28 I-11 2 I-25 7 I-26 9I-30 3 I-31 0.7 I-32 3 I-33 0.6 I-41 0.2 I-42 0.79 I-43 7 I-44 25 I-4523 I-46 29 I-47 38 I-48 7 I-49 5 I-50 3 I-51 2 I-52 7 I-53 6 I-54 7 I-551 I-56 2 I-57 0.76 I-58 1 I-59 4 I-60 3 I-61 3 I-62 1 I-63 2 I-64 2 I-652 I-66 6 I-67 15 I-68 0.4 I-69 1 I-70 21 I-71 50 I-72 72 I-73 29 I-74 2I-75 2 I-76 11 I-77 3 I-78 30 I-79 4 I-80 47 I-81 81 I-82 65 I-83 5 I-840.3 I-85 9 I-86 1 I-87 3 I-88 9 I-89 0.18 I-90 0.32 I-91 6 I-92 9 I-93 5I-94 14 I-95 16 I-96 3 I-97 2 I-98 2 I-99 2 I-100 2 I-101 2 I-102 4I-103 0.69 I-104 0.1 I-105 2 I-106 0.08 I-107 0.62 I-108 0.93 I-109 0.87I-110 8 I-111 18 I-112 5 I-113 3 I-114 4 I-115 10 I-116 10 I-117 9 I-11811 I-119 11 I-120 49 I-121 16 I-122 15 I-123 12 I-124 12 I-125 15 I-1263 I-127 3 I-128 2 I-129 2 I-130 2 I-131 0.33 I-132 0.6 I-133 13 I-134 1I-135 0.57 I-136 2 I-137 65 I-138 13 I-139 8 I-140 11 I-141 19 I-1420.55 I-143 1 I-144 0.81 I-145 0.67 I-146 4 I-147 5 I-148 3 I-149 2 I-1503 I-151 2 I-152 3 I-153 2 I-154 13 I-155 1 I-156 4 I-157 0.61 I-158 2I-159 0.41 I-160 4 I-161 0.96 I-162 2 I-163 10 I-164 14 I-165 4 I-166 11I-167 0.2 I-168 0.2 I-169 0.26 I-170 0.33 I-171 0.38 I-172 0.4 I-1730.46 I-174 0.81 I-175 0.87 I-176 0.98 I-177 1 I-178 2 I-179 2 I-180 2I-181 2 I-182 3 I-183 3 I-184 4 I-185 4 I-186 4 I-187 4 I-188 5 I-189 5I-190 6 I-191 6 I-192 6 I-193 7 I-194 7 I-195 7 I-196 8 I-197 9 I-198 11I-199 11 I-200 13 I-201 20 I-202 24 I-203 14 I-204 2 I-205 2 I-206 5I-207 10 I-208 0.68 I-209 1 I-210 0.47 I-211 3 I-212 3 I-213 4 I-2140.62 I-215 12 I-216 2 I-217 1 I-218 1 I-219 2 I-220 2 I-221 0.98 I-22232 I-223 18 I-224 18 I-225 2 I-226 2 I-227 5 I-228 8 I-229 12 I-230 13I-231 15 I-232 47 I-233 58 I-234 8 I-235 14 I-236 0.51 I-237 21 I-2381.0 I-254 2.2 IGFIR # IC50 [nM] I-291 6.0 I-292 5.0 I-293 10.0 I-294 7.0I-295 4.0 I-296 1.0 I-297 9.0 I-298 7.0 I-299 8.0 I-300 11.0 I-301 1.6I-302 0.6 I-303 0.2 I-304 1.0 I-305 2.0 I-306 1.0 I-307 1.0 I-308 0.8I-309 1.0 I-310 5.0 I-311 15.0 I-312 27.0 I-313 0.5 I-314 5.0 I-315 1.9I-316 2.0 I-317 6.0 I-318 0.4 I-319 2.0 I-320 0.9 I-321 2.0 I-322 0.5I-323 0.9 I-324 0.1 I-325 2.0 I-326 2.0 I-327 1.0 I-328 1.0 I-329 2.0I-330 3.0 I-331 1.0 I-332 1.0 I-333 2.0 I-334 0.4 I-335 3.0 I-336 4.0I-337 9.0 I-339 2.1 I-340 11.0 I-341 0.9 I-342 3.0 I-350 0.5 I-351 0.5I-352 0.8 I-353 2.0 I-354 1.0 I-355 0.5 I-356 0.8 I-357 0.7 I-358 0.7I-359 0.5 I-360 0.6 I-36I 0.4 I-362 0.3 I-363 2.0 I-364 0.6 I-365 1.0I-366 2.0 I-367 3.0 I-368 2.0 I-369 2.0 I-370 2.0 I-371 0.8 I-372 0.8I-373 0.4 I-374 11.0 I-375 9.0 I-376 0.6 I-377 0.9 I-378 6.0 I-379 6.0I-380 2.0 I-381 0.9 I-382 1.0 I-383 2.0 I-384 6.0 I-385 4.0 I-386 3.0

Cellular IGF-1R-Phosphorylation Assay

The activity of substances against the phosphorylation of IGF-1R inactivated cells is measured as follows: mouse fibroblast cells(transfected with human IGF-1R, Fibro-hIGF-1R) are cultivated instandard medium (DMEM, 10% foetal calf serum (FCS, Gibco), 1×MEMNon-Essential Amino Acids (NEAA, Gibco), 7.5% sodium hydrogen carbonate(Gibco) and 0.3 mg/mL Puromycin (Sigma)) in a humid incubator at 37° C.with 5 CO₂/95% air.

10000 Fibro-hIGF-1R cells per well in 200 μL of standard medium areseeded into 96-well plates and cultivated overnight. The next day, themedium is suction filtered and the cells are cultivated in 90 μLserum-reduced medium (DMEM, 0.5% FCS, 1×MEM NEAA, 7.5% sodium hydrogencarbonate) for a further 24 h. 10 μL of substance solution (diluted inserum-reduced medium) is added thereto, and the cells are incubated fora further 120 min in the incubator. The phosphorylation of IGF-1R isactivated for 30 min by the addition of IGF-1 (20 ng/mL in serum-reducedmedium). All further incubations are carried out at RT. The supernatantis suction filtered from the wells, and the cells are fixed in 100 μLper well of 4% paraformaldehyde (diluted in PBS). The supernatant in thewell is suction filtered and the cells are permeabilised for 5 min in300 μL per well of 0.1% TritonX-100 (diluted in PBS). The supernatantsare suction filtered once again and the cells are incubated for 20 minin quenching buffer (PBS with 0.1% TritonX-100 and 1.2 hydrogenperoxide), to inhibit the endogenous peroxidase of the cells. The cellsare washed for 5 min with 300 μL per well of PBS with 0.1% TritonX-100and then incubated for 60 min with 100 μL per well of blocking buffer(PBS with 0.1% TritonX-100 and 5% Bovine Serum Albumin (BSA)). Theblocking buffer is exchanged for 50 μL of the first antibody buffer(1/1000 dilute anti-phospho-IGF-1 receptor β (Tyr1135/1136)/insulinreceptor β (Tyr1150/1151) (19H7) rabbit monoclonal antibody from CellSignaling Technology in blocking buffer) and the plates are incubatedovernight at 4° C. The next day the plates are washed for 5 min with 300μL PBS/0.1% TritonX-100 at RT and then incubated for 60 min with 50 μLper well of the second antibody buffer (1/500 diluted Goat Anti-RabbitImmunoglobulin-Horseradish Peroxidase (HRP) (Dako) in blocking buffer)at RT. The plates are washed first for 5 min with 300 μL PBS/0.1%TritonX-100 and then for a further 5 min with 300 μL PBS at RT. Theplates are developed for 10 min with 100 μL per well of a peroxidasesolution (1:1 mixture of TMB Peroxidase Substrate and PeroxidaseSolution B from Kirkegaard & Perry Laboratories, Inc.). The reactionsare stopped with 100 μL per well of stop solution (1M phosphoric acid).The absorbance in each well is measured at 450 nm with a SpectraMaxAbsorbance Reader. EC₅₀ values for inhibiting the phosphorylation of theIGF-1R in activated cells are calculated using the programmes Fifty(Version 2) and GraphPad (Version 3.0).

Compounds (I) according to the invention generally display a goodinhibitory effect in the cellular assay described above, i.e. forexample an EC₅₀ value of less than 5 μmol/L, often less than 3 μmol/L.

Cell Proliferation Assays

Compounds were tested for their anti-proliferative effects in the TC-71(Ewing's sarcoma) and HCT 116 (colorectal carcinoma) cancer cell linesin vitro. Published scientific data has described that interference withthe Insulin-like Growth Factor-1 Receptor (IGF-1R) signaling pathwayreduces the proliferation of TC-71 cells [1]. Therefore TC-71 cellsserved as a positive control cell line for monitoring the activity ofcompounds against IGF-1R-mediated cell proliferation. In contrast,published data has demonstrated that the proliferation of HCT 116 cellsis independent of IGF-1R signaling [2]. Therefore the HCT 116 cell lineserved as a negative control.

2000 TC-71 cells or 1000 HCT 116 cells were seeded per well in 180 μLIMDM+10% foetal calf serum (FCS)+ penicillin/streptomycin into 96-wellmicrotitre plates. The plates were placed in a cell culture incubator(37° C. in a humidified atmosphere of 95% O₂/5 CO₂) overnight. Thefollowing day, serial dilutions of compounds, prepared in duplicates,were transferred onto the cell layers (controls without compound). Thecells were cultivated for a further 72 h in the cell culture incubator.20 μL of Alamar Blue™ (Serotec Ltd, Düsseldorf, Germany) was added toeach well and the plates incubated for 7 h in the cell cultureincubator. Fluorescence (extinction wavelength of 544 nm and emission at590 nm) was then measured and the normalized data fitted by iterativecalculation with a sigmoidal curve analysis program (Graph Pad Prism)with a variable Hill slope to determine the IC₅₀ values.

The EC₅₀ ranges of the following compounds were determined on TC-71cells according to this assay (“+++”<50 nM; 50 nM<“++”<250 nM; 250nM<“+”<3 μM):

EC₅₀ TC-7I # [nM] I-238 ++ I-31 +++ I-53 ++ I-54 ++ I-55 ++ I-56 + I-57+++ I-66 + I-67 ++ I-68 +++ I-69 +++ I-291 ++ I-292 ++ I-293 ++ I-294 +I-295 ++ I-296 ++ I-297 ++ I-298 ++ I-299 +++ I-300 +++ I-97 +++ I-102++ I-103 +++ I-104 +++ I-160 + I-301 +++ I-302 +++ I-303 +++ I-304 +++I-305 ++ I-306 +++ I-307 +++ I-308 +++ I-309 +++ I-310 ++ I-311 ++ I-312++ I-313 +++ I-314 ++ I-316 ++ I-317 +++ I-318 +++ I-319 +++ I-320 +++I-321 +++ I-322 +++ I-323 +++ I-324 +++ I-325 ++ I-326 ++ I-327 +++I-328 +++ I-329 +++ I-330 +++ I-331 +++ I-332 +++ I-333 + I-334 +++I-335 +++ I-336 ++ I-337 + I-338 + I-339 +++ I-340 ++ I-341 +++ I-342+++ I-203 + I-204 ++ I-208 ++ I-209 ++ I-210 +++ I-211 ++ I-212 ++ I-213++ I-214 +++ I-215 + I-216 ++ I-217 ++ I-218 +++ I-219 +++ I-220 ++I-221 +++ I-350 +++ I-351 +++ I-352 +++ I-353 +++ I-354 +++ I-355 +I-356 +++ I-357 ++ I-358 +++ I-359 +++ I-360 +++ I-361 +++ I-362 +++I-363 ++ I-364 +++ I-365 ++ I-366 ++ I-367 +++ I-368 +++ I-369 +++ I-370+++ I-371 +++ I-372 +++ I-373 ++ I-374 ++ I-375 +++ I-376 +++ I-377 +++I-378 ++ I-379 ++ I-380 ++ I-381 ++ I-382 +++ I-383 ++ I-384 ++ I-385 ++I-386 +++ I-235 +

In addition to TC-71, several other cancer cell lines from diversetissue origins, which have previously been demonstrated to be sensitiveto IGF-1R inhibition, were shown to be sensitive to compounds (I).Examples include COLO 205 (colorectal cancer) [3], LP-1 (multiplemyeloma) [4] and HL-60 (acute myeloid leukemia) [5].

REFERENCE LIST

-   1 Manara, M. C., Landuzzi, L., Nanni, P., Nicoletti, G., Zambelli,    D., Lollini, P. L., Nanni, C., Hofmann, F., Garcia-Echeverria, C.,    Picci, P. and Scotlandi, K. (2007) Preclinical in vivo study of new    insulin-like growth factor-I receptor—specific inhibitor in Ewing's    sarcoma. Clin. Cancer Res., 13, 1322-1330.-   2 Pitts, T. M., Tan, A. C., Kulikowski, G. N., Tentler, J. J.,    Brown, A. M., Flanigan, S. A., Leong, S., Coldren, C. D., Hirsch, F.    R., Varella-Garcia, M., Korch, C. and Eckhardt, S. G. (2010)    Development of an integrated genomic classifier for a novel agent in    colorectal cancer: approach to individualized therapy in early    development. Clin Cancer Res., 16, 3193-3204.-   3 Haluska, P., carboni, J. M., Loegering, D. A., Lee, F. Y.,    Wittman, M., Saulnier, M. G., to Frennesson, D. B., Kalli, K. R.,    Conover, C. A., Attar, R. M., Kaufmann, S. H., Gottardis, M. and    Erlichman, C. (2006) In vitro and in vivo antitumor effects of the    dual insulin-like growth factor-I/insulin receptor inhibitor,    BMS-554417. Cancer Res., 66, 362-371.-   4 Georgii-Hemming, P., Wiklund, H. J., Ljunggren, O. and    Nilsson, K. (1996) Insulin-like growth factor I is a growth and    survival factor in human multiple myeloma cell lines. Blood, 88,    2250-2258.-   5 Wahner Hendrickson, A. E., Haluska, P., Schneider, P. A.,    Loegering, D. A., Peterson, K. L., Attar, R., Smith, B. D.,    Erlichman, C., Gottardis, M., Karp, J. E., carboni, J. M. and    Kaufmann, S. H. (2009) Expression of insulin receptor isoform A and    insulin-like growth factor-1 receptor in human acute myelogenous    leukemia: effect of the dual-receptor inhibitor BMS-536924 in vitro.    Cancer Res., 69, 7635-7643.

On the basis of their biological properties the compounds of generalformula (I) according to the invention, their tautomers, racemates,enantiomers, diastereomers, mixtures thereof and the salts of all theabove-mentioned forms are suitable for treating diseases characterisedby excessive or abnormal cell proliferation.

Such diseases include for example: viral infections (e.g. HIV andKaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis,arthritis, Alzheimer's disease, glomerulonephritis and wound healing);bacterial, fungal and/or parasitic infections; leukaemias, lymphomas andsolid tumours (e.g. carcinomas and sarcomas), skin diseases (e.g.psoriasis); diseases based on hyperplasia which are characterised by anincrease in the number of cells (e.g. fibroblasts, hepatocytes, bonesand bone marrow cells, cartilage or smooth muscle cells or epithelialcells (e.g. endometrial hyperplasia)); bone diseases and cardiovasculardiseases (e.g. restenosis and hypertrophy). They are also suitable forprotecting proliferating cells (e.g. hair, intestinal, blood andprogenitor cells) from DNA damage caused by radiation, UV treatmentand/or cytostatic treatment.

For example, the following cancers may be treated with compoundsaccording to the invention, without being restricted thereto: braintumours such as for example acoustic neurinoma, astrocytomas such aspilocytic astrocytomas, fibrillary astrocytoma, protoplasmicastrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma andglioblastoma, brain lymphomas, brain metastases, hypophyseal tumour suchas prolactinoma, HGH (human growth hormone) producing tumour and ACTHproducing tumour (adrenocorticotropic hormone), craniopharyngiomas,medulloblastomas, meningeomas and oligodendrogliomas; nerve tumours(neoplasms) such as e.g. tumours of the vegetative nervous system suchas neuroblastoma sympathicum, ganglioneuroma, paraganglioma(pheochromocytoma, chromaffinoma) and glomus-caroticum tumour, tumourson the peripheral nervous system such as amputation neuroma,neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignantSchwannoma, as well as tumours of the central nervous system such asbrain and bone marrow tumours; intestinal cancer such as for examplecarcinoma of the rectum, colon carcinoma, colorectal carcinoma, analcarcinoma, carcinoma of the large bowel, tumours of the small intestineand duodenum; eyelid tumours such as basalioma or basal cell carcinoma;pancreatic cancer or carcinoma of the pancreas; bladder cancer orcarcinoma of the bladder; lung cancer (bronchial carcinoma) such as forexample small-cell bronchial carcinomas (oat cell carcinomas) andnon-small cell bronchial carcinomas (NSCLC) such as plate epithelialcarcinomas, adenocarcinomas and large-cell bronchial carcinomas; breastcancer such as for example mammary carcinoma such as infiltrating ductalcarcinoma, colloid carcinoma, lobular invasive carcinoma, tubularcarcinoma, adenocystic carcinoma and papillary carcinoma; non-Hodgkin'slymphomas (NHL) such as for example Burkitt's lymphoma, low-malignancynon-Hodgkin's lymphomas (NHL) and mucosis fungoides; uterine cancer orendometrial carcinoma or corpus carcinoma; CUP syndrome (Cancer ofUnknown Primary); ovarian cancer or ovarian carcinoma such as mucinous,endometrial or serous cancer; gall bladder cancer; bile duct cancer suchas for example Klatskin tumour; testicular cancer such as for exampleseminomas and non-seminomas; lymphoma (lymphosarcoma) such as forexample malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas(NHL) such as chronic lymphatic leukaemia, leukaemicreticuloendotheliosis, immunocytoma, plasmocytoma (multiple myeloma),immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides, large-cellanaplastic lymphoblastoma and lymphoblastoma; laryngeal cancer such asfor example tumours of the vocal cords, supraglottal, glottal andsubglottal laryngeal tumours; bone cancer such as for exampleosteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma,osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giantcell tumour, chondrosarcoma, osteosarcoma, Ewing's sarcoma,reticulo-sarcoma, plasmocytoma, fibrous dysplasia, juvenile bone cystsand aneurysmatic bone cysts; head and neck to tumours such as forexample tumours of the lips, tongue, floor of the mouth, oral cavity,gums, palate, salivary glands, throat, nasal cavity, paranasal sinuses,larynx and middle ear; liver cancer such as for example liver cellcarcinoma or hepatocellular carcinoma (HCC); leukaemias, such as forexample acute leukaemias such as acute lymphatic/lymphoblastic leukaemia(ALL), acute myeloid leukaemia (AML); chronic leukaemias such as chroniclymphatic leukaemia (CLL), chronic myeloid leukaemia (CML); stomachcancer or gastric carcinoma such as for example papillary, tubular andmucinous adenocarcinoma, signet ring cell carcinoma, adenosquamouscarcinoma, small-cell carcinoma and undifferentiated carcinoma;melanomas such as for example superficially spreading, nodular,lentigo-maligna and acral-lentiginous melanoma; renal cancer such ase.g. kidney cell carcinoma or hypernephroma or Grawitz's tumour;oesophageal cancer or carcinoma of the oesophagus; penile cancer;prostate cancer; throat cancer or carcinomas of the pharynx such as forexample nasopharynx carcinomas, oropharynx carcinomas and hypopharynxcarcinomas; retinoblastoma; vaginal cancer or vaginal carcinoma; plateepithelial carcinomas, adenocarcinomas, in situ carcinomas, malignantmelanomas and sarcomas; thyroid carcinomas such as for examplepapillary, follicular and medullary thyroid carcinoma, as well asanaplastic carcinomas; spinalioma, epidormoid carcinoma and plateepithelial carcinoma of the skin; thymomas, cancer of the urethra andcancer of the vulva.

The new compounds may be used for the prevention, short-term orlong-term treatment of the above-mentioned diseases, optionally also incombination with radiotherapy or other “state-of-the-art” compounds,such as e.g. cytostatic or cytotoxic substances, cell proliferationinhibitors, anti-angiogenic substances, steroids or antibodies.

The compounds of general formula (I) may be used on their own or incombination with other active substances according to the invention,optionally also in combination with other pharmacologically activesubstances.

Chemotherapeutic agents which may be administered in combination withthe compounds according to the invention, include, without beingrestricted thereto, hormones, hormone analogues and antihormones (e.g.tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate,flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproteroneacetate, finasteride, buserelin acetate, fludrocortisone,fluoxymesterone, medroxy-to progesterone, octreotide), aromataseinhibitors (e.g. anastrozole, letrozole, liarozole, vorozole,exemestane, atamestane), LHRH agonists and antagonists (e.g. goserelinacetate, luprolide), inhibitors of growth factors (growth factors suchas for example “platelet derived growth factor (PDGF)”, “fibroblastgrowth factor (FGF)”, “vascular endothelial growth factor (VEGF)”,“epidermal growth factor (EGF)”, “insuline-like growth factors (IGF)”,“human epidermal growth factor (HER, e.g. HER2, HER3, HER4)” and“hepatocyte growth factor (HGF)”), inhibitors are for example “growthfactor” antibodies, “growth factor receptor” antibodies and tyrosinekinase inhibitors, such as for example cetuximab, gefitinib, imatinib,lapatinib and trastuzumab); antimetabolites (e.g. antifolates such asmethotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil,capecitabin and gemcitabin, purine and adenosine analogues such asmercaptopurine, thioguanine, cladribine and pentostatin, cytarabine,fludarabine); antitumour antibiotics (e.g. anthracyclins such asdoxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C,bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives(e.g. cisplatin, oxaliplatin, carboplatin); alkylation agents (e.g.estramustin, meclorethamine, melphalan, chlorambucil, busulphan,dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureassuch as for example carmustin and lomustin, thiotepa); antimitoticagents (e.g. Vinca alkaloids such as for example vinblastine, vindesin,vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel);tubuline inhibitors; PARP inhibitors, topoisomerase inhibitors (e.g.epipodophyllotoxins such as for example etoposide and etopophos,teniposide, amsacrin, topotecan, irinotecan, mitoxantron),serine/threonine kinase inhibitors (e.g. PDK 1 inhibitors, B-Rafinhibitors, mTOR inhibitors, mTORC1 inhibitors, PI3K inhibitors, dualmTOR/PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1inhibitors, inhibitors of CDKs, Aurora kinase inhibitors), tyrosinekinase inhibitors (e.g. PTK2/FAK inhibitors), protein proteininteraction inhibitors (e.g. IAP, Mcl-1, MDM2/MDMX), MEK inhibitors, ERKinhibitors, IGF-1R inhibitors, ErbB receptor inhibitors, rapamycinanalogs (e.g. everolimus, temsirolimus, ridaforolimus, sirolimus) andvarious chemotherapeutic agents such as amifostin, anagrelid, clodronat,filgrastin, interferon, interferon alpha, leucovorin, rituximab,procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer.

Other possible combination partners are 2-chlorodesoxyadenosine,2-fluorodesoxy-cytidine, 2-methoxyoestradiol, 2C4,3-alethine,131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B,A 105972, A 204197, abiraterone, to aldesleukin, alitretinoin,allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole,AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene,atamestane, atrasentan, auristatin PE, AVLB, AZ10992, ABX-EGF, AMG-479(ganitumab), ARRY 162, ARRY 438162, ARRY-300, ARRY-142886/AZD-6244(selumetinib), ARRY-704/AZD-8330, AR-12, AR-42, AS-703988, AXL-1717,AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ 680, AS-703026 (primasertib),avastin, AZD-2014, azacytidine, azaepothilone B, azonafide, BAY-43-9006,BAY 80-6946, BBR-3464, BBR-3576, bevacizumab, BEZ-235, biricodardicitrate, BCX-1777, BKM-120, bleocin, BLP-25, BMS-184476, BMS-247550,BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW2992 (afatinib, tomtovok), BIBF 1120 (vargatef), B1 836845, B1 2536, B16727, B1 836845, B1 847325, B1 853520, BIIB-022, bleomycinic acid,bleomycin A, bleomycin B, brivanib, bryostatin-1, bortezomib,brostallicin, busulphan, BYL-719, CA-4 prodrug, CA-4, CapCell,calcitriol, canertinib, canfosfamide, capecitabine,carboxyphthalatoplatin, CCl-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1cefixime, ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin,CH4987655/RO-4987655, chlorotrianisene, cilengitide, ciclosporin,CDA-II, CDC-394, CKD-602, CKI-27, clofarabin, colchicin, combretastatinA4, COT inhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin52, CTP-37, CTLA-4 monoclonal antibodies, CP-461, CV-247,cyanomorpholinodoxorubicin, cytarabine, D 24851, decitabine,deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide,desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstilbestrol,diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-7423, E7010,E-6201, edatrexat, edotreotide, efaproxiral, eflornithine, EGFRinhibitors, EKB-569, EKB-509, enzastaurin, elsamitrucin, epothilone B,epratuzumab, ER-86526, erlotinib, ET-18-OCH3, ethynylcytidine,ethynyloestradiol, exatecan, exatecan mesylate, exemestane, exisulind,fenretinide, figitumumab, floxuridine, folic acid, FOLFOX, FOLFOX4,FOLFIRI, formestane, fotemustine, galarubicin, gallium maltolate,gefinitib, gemtuzumab, gimatecan, glufosfamide, GCS-100, GDC-0623,GDC-0941 (pictrelisib), GDC-0980, GDC-0032, GDC-0068, GDC-0349,GDC-0879, G17DT immunogen, GMK, GPX-100, gp100-peptide vaccines,GSK-5126766, GSK-690693, GSK-1120212 (trametinib), GSK-2118436(dabrafenib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183,GSK-2141795, GW2016, granisetron, herceptine, hexamethylmelamine,histamine, homoharringtonine, hyaluronic acid, hydroxyurea,hydroxyprogesterone caproate, ibandronate, ibritumomab, idatrexate,idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A12(cixutumumab), immunol, indisulam, interferon alpha-2a, interferonalpha-2b, pegylated interferon alpha-2b, interleukin-2, INK-1117,INK-128, INSM-18, ionafarnib, ipilimumab, iproplatin, irofulven,isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2,JSF-154, J-107088, conjugated oestrogens, kahalid F, ketoconazole,KW-2170, KW-2450, lobaplatin, leflunomide, lenograstim, leuprolide,leuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin,lometrexol, losoxantrone, LU 223651, lurtotecan, LY-S6AKT1, LY-2780301,mafosfamide, marimastat, mechloroethamine, MEK inhibitors, MEK-162,methyltestosteron, methylprednisolone, MEDI-573, MEN-10755, MDX-H210,MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin,mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, motexaf ingadolinium, MS-209, MS-275, MX6, neridronate, neratinib, Nexavar,neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin,N-acetylcysteine, 06-benzylguanine, oblimersen, omeprazole, oncophage,oncoVEX^(GM-CSF), ormiplatin, ortataxel, OX44 antibodies, OSI-027,OSI-906 (linsitinib), 4-1BB antibodies, oxantrazole, oestrogen,panitumumab, patupilone, pegfilgrastim, PCK-3145, pegfilgrastim,PBI-1402, PBI-05204, PDO325901, PD-1 antibodies, PEG-paclitaxel,albumin-stabilized paclitaxel, PEP-005, PF-05197281, PF-05212384,PF-04691502, PHT-427, P-04, PKC412, P54, P1-88, pelitinib, pemetrexed,pentrix, perifosine, perillylalcohol, pertuzumab, PI3K inhibitors,PI3K/mTOR inhibitors, PG-TXL, PG2, PLX-4032/R0-5185426 (vemurafenib),PLX-3603/R0-5212054, PT-100, PWT-33597, PX-866, picoplatin,pivaloyloxymethylbutyrate, pixantrone, phenoxodiol 0, PKI166,plevitrexed, plicamycin, polyprenic acid, porfiromycin, prednisone,prednisolone, quinamed, quinupristin, R115777, RAF-265, ramosetron,ranpirnase, RDEA-119/BAY 869766, RDEA-436, rebeccamycin analogues,receptor tyrosine kinase (RTK) inhibitors, revimid, RG-7167, RG-7304,RG-7421, RG-7321, RG 7440, rhizoxin, rhu-MAb, rinfabate, risedronate,rituximab, robatumumab, rofecoxib, RO-31-7453, RO-5126766, RO-5068760,RPR 109881A, rubidazone, rubitecan, R-flurbiprofen, RX-0201, S-9788,sabarubicin, SAHA, sargramostim, satraplatin, SB 408075, Se-015/Ve-015,SU5416, SU6668, SDX-101, semustin, seocalcitol, SM-11355, SN-38,SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, sorafenib, spiroplatin,squalamine, suberanilohydroxamic acid, sutent, T 900607, T 138067,TAK-733, TAS-103, tacedinaline, talaporf in, Tarceva, tariquitar,tasisulam, taxotere, taxoprexin, tazarotene, tegafur, temozolamide,tesmilifene, testosterone, testosterone propionate, tesmilifene,tetraplatin, tetrodotoxin, tezacitabine, thalidomide, theralux,therarubicin, thymalfasin, thymectacin, tiazofurin, tipifarnib,tirapazamine, tocladesine, tomudex, toremofin, trabectedin,TransMID-107, transretinic acid, traszutumab, tremelimumab, tretinoin,triacetyluridine, triapine, triciribine, trimetrexate, TLK-286TXD 258,tykerb/tyverb, urocidin, valrubicin, vatalanib, vincristine, vinflunine,virulizin, WX-UK1, WX-554, vectibix, xeloda, XELOX, XL-147, XL-228,XL-281, XL-518/R-7420/GDC-0973, XL-765, YM-511, YM-598, ZD-4190,ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474,zoledronat and zosuquidar.

Suitable preparations include for example tablets, capsules,suppositories, solutions-particularly solutions for injection (s.c.,i.v., i.m.) and infusion—elixirs, emulsions or dispersible powders. Thecontent of the pharmaceutically active compound(s) should be in therange from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of thecomposition as a whole, i.e. in amounts which are sufficient to achievethe dosage range specified below. The doses specified may, if necessary,be given several times a day.

Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g.with the addition of isotonic agents, preservatives such asp-hydroxybenzoates, or stabilisers such as alkali metal salts ofethylenediamine tetraacetic acid, optionally using emulsifiers and/ordispersants, whilst if water is used as the diluent, for example,organic solvents may optionally be used as solvating agents ordissolving aids, and transferred into injection vials or ampoules orinfusion bottles.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

The preparations are administered by the usual methods, preferably byoral or transdermal route, most preferably by oral route. For oraladministration the tablets may, of course contain, apart from theabovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

For parenteral use, solutions of the active substances with suitableliquid carriers may be used.

The dosage for intravenous use is from 1-1000 mg per hour, preferablybetween 5 and 500 mg per hour.

However, it may sometimes be necessary to depart from the amountsspecified, depending on the body weight, the route of administration,the individual response to the drug, the nature of its formulation andthe time or interval over which the drug is administered. Thus, in somecases it may be sufficient to use less than the minimum dose givenabove, whereas in other cases the upper limit may have to be exceeded.When administering large amounts it may be advisable to divide them upinto a number of smaller doses spread over the day.

The formulation examples which follow illustrate the present inventionwithout restricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance according to formula (I) 100 mglactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesiumstearate 5 mg 500 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tablets per tablet active substance according to formula (I) 80 mglactose 55 mg corn starch 190 mg microcrystalline cellulose 35 mgpolyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesiumstearate 2 mg 400 mg

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. Thesodiumcarboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize.

C) Ampoule solution active substance according to formula (I) 50 mgsodium chloride 50 mg water for inj. 5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

1. A compound of the formula (I)

wherein R⁵ is selected from among trifluoromethyl and halogen; R⁶, R⁷and R⁸ are independently selected in each case from among hydrogen andC₁₋₄alkyl or R⁶ and R⁷ together with the carbon atom to which they bondform a saturated, 3-5 membered hydrocarbon ring; ring system A isselected from among C₆₋₁₀aryl, 3-14 membered heterocyclyl and 5-12membered heteroaryl; each R⁹ is independently selected in each case fromamong C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, halogen and—CN; m denotes 0, 1, 2 or 3; L¹ is selected from among a bond,—(CH₂)_(n)—O, —(CH₂)_(n)—NH, —(CH₂)_(n)—NH—C(O), —(CH₂)_(n)—C(O)—NH,—(CH₂)_(n)— and —(CH₂)_(n)—C(O), while in the present nomenclature thelinker group L¹ on the right binds to the ring system A; n denotes 0, 1,2 or 3; ring system B is selected from among 4-10 membered, saturated orunsaturated heterocyclyl and phenyl; each R¹⁰ is independently selectedin each case from among R^(a) and R^(b); p denotes 0, 1, 2 or 3; eachR^(a) independently denotes a group optionally substituted by one ormore identical or different R^(b) and/or R^(c) selected from amongC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl,C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; eachR^(b) is independently selected in each case from among —OR^(c),—SR^(c), —NR^(c)R^(c), halogen, —CN, —NO₂, —C(O)R^(c), —C(O)OR^(c),—C(O)NR^(c)R^(c), —C(NR^(f))NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c),—S(O)₂R^(c), —S(O)₂NR^(c)R^(c), —NR^(f)C(O)R^(c), —NR^(f)C(O)OR^(c),—NR^(f)C(O)NR^(c)R^(c), —NR^(f)C(NR^(f))NR^(c)R^(c) and—NR^(f)S(O)₂R^(c), as well as the bivalent substituent ═O, while thelatter may only be a substituent in non-aromatic ring systems; eachR^(c) independently denotes hydrogen or a group optionally substitutedby one or more identical or different R^(d) and/or R^(e) selected fromamong C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl,C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 memberedheterocyclyl; each R^(d) is independently selected in each case fromamong —OR^(e), —SR^(e), —NR^(e)R^(e), halogen, —CN, —NO₂, —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(e), —C(NR^(f))NR^(e)R^(e), —OC(O)R^(e),—OC(O)OR^(e), —S(O)₂R^(e), —S(O)₂NR^(e)R^(e), —NR^(f)C(O)R^(e),—NR^(f)C(O)OR^(e), —NR^(f)C(O)NR^(e)R^(e), —NR^(f)C(NR^(f))NR^(e)R^(e)and —NR^(f)S(O)₂R^(e), as well as the bivalent substituent ═O, while thelatter may only be a substituent in non-aromatic ring systems; eachR^(e) independently denotes hydrogen or a group optionally substitutedby one or more identical or different R^(f) selected from amongC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl,C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, andeach R^(f) is independently selected in each case from among hydrogenand C₁₋₆alkyl, while the compounds (I) may optionally also occur in theform of their tautomers, racemates, enantiomers, diastereomers ormixtures thereof, or as the respective salts of all the above-mentionedforms.
 2. The compound according to claim 1, wherein R⁵ denotestrifluoromethyl.
 3. The compound according to claim 1, wherein R⁵denotes chlorine.
 4. The compound according to claim 1, wherein R⁵denotes bromine.
 5. The compound according to claim 1, wherein R⁶ and R⁷in each case denote methyl and R⁸ denotes hydrogen.
 6. The compoundaccording to claim 1, wherein R⁶, R⁷ and R⁸ in each case denotehydrogen.
 7. The compound according to claim 1, wherein R⁶ and R⁷together with the carbon atom to which they bond form a cyclopropyl ringand R⁸ denotes hydrogen.
 8. The compound according to claim 1, whereinring system A is selected from among phenyl and 5-6 membered heteroaryl.9. The compound according to claim 8, wherein ring system A is a phenyl.10. The compound according to claim 8, wherein ring system A is a 5-6membered, nitrogen-containing heteroaryl.
 11. The compound according toclaim 10, wherein ring system A is a pyridyl or pyrazolyl.
 12. Thecompound according to claim 1, wherein m has the value
 0. 13. Thecompound according to claim 1, wherein m has the value 1 or 2 and R⁹ isselected from among halogen, C₁₋₄alkyl and C₁₋₄alkoxy.
 14. The compoundaccording to claim 13, wherein m has the value 1 or 2 and R⁹ is selectedfrom among C₁₋₄alkyl and C₁₋₄alkoxy.
 15. The compound according to claim14, wherein m has the value 1 or 2 and R⁹ is selected from among methyl,ethyl, methoxy and ethoxy.
 16. The compound according to claim 1,wherein ring system A and the m groups R⁹ together denote

R^(9a) is selected from among hydrogen, C₁₋₄alkyl and C₁₋₄alkoxy andR^(9b) is selected from among hydrogen and C₁₋₄alkyl.
 17. The compoundaccording to claim 16, wherein ring system A and the m groups R⁹together denote

R^(9a) is selected from among hydrogen, methyl, ethyl, methoxy andethoxy and R^(9b) is selected from among hydrogen, methyl and ethyl. 18.The compound according to claim 1, wherein ring system A and the mgroups R⁹ together denote


19. The compound according to claim 1, wherein L¹ is selected from amonga bond, —(CH₂)₂—O, —NH—C(O), —C(O)—NH— and —C(O), while in the presentnomenclature the linker group L¹ on the right binds to the ring systemA.
 20. The compound according to claim 19, wherein L¹ corresponds to abond.
 21. The compound according to claim 19, wherein L¹ is selectedfrom among —(CH₂)₂—O, —NH—C(O)— and —C(O)—.
 22. The compound accordingto claim 1, wherein ring system B is a 4-10 membered, saturated orunsaturated heterocyclyl.
 23. The compound according to claim 22,wherein ring system B is a 5-7 membered, saturated andnitrogen-containing heterocyclyl.
 24. The compound according to claim23, wherein ring system B is selected from among piperidinyl,piperazinyl, pyrrolidinyl, morpholinyl and2,5-diaza-bicyclo[2,2,1]heptyl.
 25. The compound according to claim 1,wherein p has the value
 0. 26. The compound according to claim 1,wherein p has the value 1 or 2, each R¹⁰ is independently selected ineach case from among R^(a) and R^(b); each R^(a) independently denotes agroup optionally substituted by one or more identical or different R^(b)and/or R^(c) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-14membered heterocyclyl; each R^(b) is independently selected in each casefrom among —OR^(c), —NR^(c)R^(c), halogen, —CN, —C(O)R^(c), —C(O)OR^(c),—C(O)NR^(c)R^(c), —S(O)₂R^(c) and —S(O)₂NR^(c)R^(c), as well as thebivalent substituent ═O, while the latter may only be a substituent innon-aromatic ring systems; each R^(c) independently denotes hydrogen ora group optionally substituted by one or more identical or differentR^(d) and/or R^(e) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, 5-12membered heteroaryl and 3-14 membered heterocyclyl; each R^(d) isindependently selected in each case from among —OR^(e), —NR^(e)R^(e),—CN, —C(O)R^(e), —C(O)OR^(e) and —NR^(f)C(O)OR^(e), as well as thebivalent substituent ═O, while the latter may only be a substituent innon-aromatic ring systems; each R^(e) independently denotes hydrogen ora group optionally substituted by one or more identical or differentR^(f) selected from among C₁₋₆alkyl, C₆₋₁₀aryl, 5-12 membered heteroaryland 3-14 membered heterocyclyl, and each R^(f) is independently selectedin each case from among hydrogen and C₁₋₆alkyl.
 27. The compoundaccording to claim 1, wherein p has the value 1 or 2, each R¹⁰ isindependently selected in each case from among R^(a) and R^(b); eachR^(a) independently denotes a group optionally substituted by one ormore identical or different R^(b) and/or R^(c) selected from amongC₁₋₆alkyl, C₃₋₆cycloalkyl and 4-7 membered heterocyclyl; each R^(b) isindependently selected in each case from among —OR^(c), —NR^(c)R^(c),halogen, —CN, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —S(O)₂R^(c) and—S(O)₂NR^(c)R^(c), as well as the bivalent substituent ═O, while thelatter may only be a substituent in non-aromatic ring systems; eachR^(c) independently denotes hydrogen or a group optionally substitutedby one or more identical or different R^(d) and/or R^(e) selected fromamong C₁₋₆alkyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl and 4-7membered heterocyclyl; each R^(d) is independently selected in each casefrom among —OR^(e), —NR^(e)R^(e), —CN, —C(O)R^(e), —C(O)OR^(e) and—NR^(f)C(O)OR^(e), as well as the bivalent substituent ═O, while thelatter may only be a substituent in non-aromatic ring systems; eachR^(e) independently denotes hydrogen or a group optionally substitutedby one or more identical or different R^(f) selected from amongC₁₋₆alkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocyclyl, and each R^(f) is independently selected in each case fromamong hydrogen and C₁₋₆alkyl.
 28. The compound according to one ofclaims 1, 26 or 27, wherein p has the value
 1. 29. The compoundaccording to claim 1, wherein ring system B and the p groups R¹⁰together denote

each R¹⁰ is independently selected in each case from among R^(a) andR^(b); each R^(a) independently denotes a group optionally substitutedby one or more identical or different R^(b) and/or R^(c) selected fromamong C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl,C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 memberedheterocyclyl; each R^(b) is independently selected in each case fromamong —OR^(c), —SR^(c), —NR^(c)R^(c), halogen, —CN, —NO₂, —C(O)R^(c),—C(O)OR^(c), —C(O)NR^(c)R^(c), —C(NR^(f))NR^(c)R^(c), —OC(O)R^(c),—OC(O)OR^(c), —S(O)₂R^(c), —S(O)₂NR^(c)R^(c), —NR^(f)C(O)R^(c),—NR^(f)C(O)OR^(c), —NR^(f)C(O)NR^(c)R^(c), —NR^(f)C(NR^(f))NR^(c)R^(c)and —NR^(f)S(O)₂R^(c), as well as the bivalent substituent ═O, while thelatter may only be a substituent in non-aromatic ring systems; eachR^(c) independently denotes hydrogen or a group optionally substitutedby one or more identical or different R^(d) and/or R^(e) selected fromamong C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl,C₄₋₁₀cycloalkenyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 memberedheterocyclyl; each R^(d) is independently selected in each case fromamong —OR^(e), —SR^(e), —NR^(e)R^(e), halogen, —CN, —NO₂, —C(O)R^(e),—C(O)OR^(e), —C(O)NR^(e)R^(e), —C(NR^(f))NR^(e)R^(e), —OC(O)R^(e),—OC(O)OR^(e), —S(O)₂R^(e), —S(O)₂NR^(e)R^(e), —NR^(f)C(O)R^(e),—NR^(f)C(O)OR^(e), —NR^(f)C(O)NR^(e)R^(e), —NR^(f)C(NR^(f))NR^(e)R^(e)and —NR^(f)S(O)₂R^(e), as well as the bivalent substituent ═O, while thelatter may only be a substituent in non-aromatic ring systems; eachR^(e) independently denotes hydrogen or a group optionally substitutedby one or more identical or different R^(f) selected from amongC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl,C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, andeach R^(f) is independently selected in each case from among hydrogenand C₁₋₆alkyl.
 30. The compound according to claim 29, wherein ringsystem B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among R^(a) andR^(b); each R^(a) independently denotes a group optionally substitutedby one or more identical or different R^(b) and/or R^(c) selected fromamong C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-14 membered heterocyclyl; eachR^(b) is independently selected in each case from among —OR^(c),—NR^(c)R^(c), halogen, —CN, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c),—S(O)₂R^(c) and —S(O)₂NR^(c)R^(c), as well as the bivalent substituent═O, while the latter may only be a substituent in non-aromatic ringsystems; each R^(c) independently denotes hydrogen or a group optionallysubstituted by one or more identical or different R^(d) and/or R^(e)selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, 5-12 membered heteroaryland 3-14 membered heterocyclyl; each R^(d) is independently selected ineach case from among —OR^(e), —NR^(e)R^(e), —CN, —C(O)R^(e), —C(O)OR^(e)and —NR^(f)C(O)OR^(e), as well as the bivalent substituent ═O, while thelatter may only be a substituent in non-aromatic ring systems; eachR^(e) independently denotes hydrogen or a group optionally substitutedby one or more identical or different R^(f) selected from amongC₁₋₆alkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 memberedheterocyclyl, and each R^(f) is independently selected in each case fromamong hydrogen and C₁₋₆alkyl.
 31. The compound according to claim 30,wherein ring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among R^(a) andR^(b); each R^(a) independently denotes a group optionally substitutedby one or more identical or different R^(b) and/or R^(c) selected fromamong C₁₋₆alkyl, C₃₋₆cycloalkyl and 4-7 membered heterocyclyl; eachR^(b) is independently selected in each case from among —OR^(c),—NR^(c)R^(c), halogen, —CN, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c),—S(O)₂R^(c) and —S(O)₂NR^(c)R^(c), as well as the bivalent substituent═O, while the latter may only be a substituent in non-aromatic ringsystems; each R^(c) independently denotes hydrogen or a group optionallysubstituted by one or more identical or different R^(d) and/or R^(e)selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryland 4-7 membered heterocyclyl; each R^(d) is independently selected ineach case from among —OR^(e), —NR^(e)R^(e), —CN, —C(O)R^(e), —C(O)OR^(e)and —NR^(f)C(O)OR^(e), as well as the bivalent substituent ═O, while thelatter may only be a substituent in non-aromatic ring systems; eachR^(e) independently denotes hydrogen or a group optionally substitutedby one or more identical or different R^(f) selected from amongC₁₋₆alkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocyclyl, and each R^(f) is independently selected in each case fromamong hydrogen and C₁₋₆alkyl.
 32. The compound according to claim 1,wherein ring system B and the p groups R¹⁰ together denote

each R¹⁰ is independently selected in each case from among—C(O)—C₁₋₄alkyl, hydrogen, C₁₋₆alkyl (CN), C₁₋₆haloalkyl—C(O)—O—C₁₋₄alkyl, —COOH, (C₁₋₄alkyl)₂N—C₁₋₄alkylene-C(O),(C₁₋₄alkyl)NH—C₁₋₄alkylene-C(O), H₂N—C₁₋₄alkylene-C(O),HO—C₁₋₄alkylene-C(O), —C(O)—N(C₁₋₄alkyl)₂, —C(O)—NH(C₁₋₄alkyl),—C(O)NH₂, C₁₋₄alkyl-O—C₁₋₄alkylene-C(O), 4-6 membered heterocyclyl(optionally substituted by C₁₋₄alkyl, C₃₋₆cycloalkyl or 3-6 memberedheterocyclyl), C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl, HO—C₂₋₄alkyl,C₁₋₄alkyl-O—C₂₋₄alkyl, HO—C₂₋₄haloalkyl, C₁₋₄alkyl-S(O)₂,C₁₋₄alkyl-NH—C(O)—C₁₋₄alkyl, H₂N—C(O)—C₁₋₄alkyl andC₁₋₄alkyl-S(O)₂—C₁₋₄alkyl.
 33. The compound according to claim 32,wherein ring system B and the p groups R¹⁰ together denote


34. The compound according to claim 1, wherein ring system B and the pgroups R¹⁰ together denote

each R¹⁰ is independently selected in each case from amongC₁₋₄alkyl-O—C₂₋₄alkylene-NH, C₁₋₄alkyl-O—C₂₋₄alkylene-N(C₁₋₄alkyl),HO—C₂₋₄alkylene-N(C₁₋₄alkyl), HO—C₂₋₄alkylene-NH, 4-6 memberedheterocyclyl (optionally substituted by C₁₋₄alkyl, 3-6 memberedheterocyclyl, halogen, —OH, —CN, C₁₋₄alkoxy, —N(C₁₋₄alkyl)₂ orC₃₋₆cycloalkyl), (C₁₋₄alkyl)₂N—C₂₋₄alkylene-N(C₁₋₄alkyl),(C₁₋₄alkyl)₂N—C₂₋₄alkylene-NH, —N(C₁₋₄alkyl)₂, —NH(C₁₋₄alkyl), C₁₋₄alkyl-NH—C(O)— and (C₁₋₄alkyl)₂N—C(O)—.
 35. A compound, orpharmaceutically acceptable salts thereof, selected from among:


36. The compound according to claim 1 wherein the compound is apharmaceutically acceptable salt thereof.
 37. A method of treating acancer selected from hepatocellular carcinomas (HCC), non-small celllung cancer (NSCLC), breast cancer and prostate cancer comprisingadministering to a patient a therapeutically effective amount of acompound according to claim 1 or the pharmaceutically acceptable saltsthereof.
 38. The method according to claim 37 wherein the patient is ahuman being.
 39. A pharmaceutical composition comprising atherapeutically effective amount of a compound according to claim 1 orthe pharmaceutically acceptable salts thereof optionally in combinationwith conventional excipients and/or carriers.
 40. The pharmaceuticalcomposition according to claim 39 and at least one other cytostatic orcytotoxic active substance, different from formula (I) of claim 1.